Trends and targets in antiviral phototherapy

Arno Wiehe *ab, Jessica M. O'Brien c and Mathias O. Senge *c
abiolitec research GmbH, Otto-Schott-Str. 15, 07745 Jena, Germany. E-mail: arno.wiehe@biolitec.com
bInstitut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
cMedicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin, St. James's Hospital, Dublin 8, Ireland. E-mail: sengem@tcd.ie; Web: http://www.twitter.com/mathiassenge

Received 9th May 2019 , Accepted 31st July 2019

First published on 9th August 2019


Photodynamic therapy (PDT) is a well-established treatment option in the treatment of certain cancerous and pre-cancerous lesions. Though best-known for its application in tumor therapy, historically the photodynamic effect was first demonstrated against bacteria at the beginning of the 20th century. Today, in light of spreading antibiotic resistance and the rise of new infections, this photodynamic inactivation (PDI) of microbes, such as bacteria, fungi, and viruses, is gaining considerable attention. This review focuses on the PDI of viruses as an alternative treatment in antiviral therapy, but also as a means of viral decontamination, covering mainly the literature of the last decade. The PDI of viruses shares the general action mechanism of photodynamic applications: the irradiation of a dye with light and the subsequent generation of reactive oxygen species (ROS) which are the effective phototoxic agents damaging virus targets by reacting with viral nucleic acids, lipids and proteins. Interestingly, a light-independent antiviral activity has also been found for some of these dyes. This review covers the compound classes employed in the PDI of viruses and their various areas of use. In the medical area, currently two fields stand out in which the PDI of viruses has found broader application: the purification of blood products and the treatment of human papilloma virus manifestations. However, the PDI of viruses has also found interest in such diverse areas as water and surface decontamination, and biosafety.


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Arno Wiehe

Arno Wiehe, Dr rer. nat., M.D.R.A., studied chemistry, history, and educational science at the Freie Universität Berlin. After the state examination in chemistry and history he focused on chemistry, receiving his Dr rer. nat. in 1997 from the Freie Universität Berlin with Prof. H. Kurreck. This was followed by postdoctoral studies with Prof. B. Röder, Humboldt Universität, Department of Physics, and Prof. M. O. Senge, Universität Potsdam. In 2001 he joined the biolitec AG as a research scientist. 2003–2005, during a part-time study at the Rheinische Friedrich-Wilhelms-Universität in Bonn he gained an additional qualification as master of drug regulatory affairs (M.D.R.A.). His research interests are synthetic organic chemistry, dye applications in medicine and biology, and drug development.

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Jessica M. O'Brien

Jessica O'Brien received her B.A. in Medicinal Chemistry from Trinity College Dublin in 2016 and remained there for her postgraduate studies. Currently in the 3rd year of her PhD, her research is focused on porphyrin synthesis and functionalization, as well as the design of photosensitizers for PACT. She is also actively involved in outreach activities and is an ambassador for Trinity College Dublin.

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Mathias O. Senge

Mathias O. Senge, Dipl.-Chem., M.A., Dr rer. nat., F.T.C.D., studied chemistry and biochemistry in Freiburg, Amherst, Marburg, and Lincoln. After a Ph.D. from the Philipps Universität Marburg (1989) and postdoctoral studies with K. M. Smith at UC Davis he received his habilitation in Organic Chemistry in 1996 at the Freie Universität Berlin. From 1996 on he was a Heisenberg fellow at the Freie Universität Berlin and UC Davis and held visiting professorships at Greifswald and Potsdam. In 2002 he was appointed Professor of Organic Chemistry at the Universität Potsdam and since 2005 holds the Chair of Organic Chemistry at Trinity College Dublin. He was the recipient of fellowships from the Studienstiftung des Deutschen Volkes, the Deutsche Forschungsgemeinschaft, and Science Foundation Ireland (Research Professor 2005–2009). His interests are synthetic organic chemistry, the (bio)chemistry of tetrapyrroles, photobiology and photomedicine, structural chemistry, and history of science.


1. Introduction

1.1 Background and scope

With 2015 as the International Year of the Light, and in 2018 the declaration by the UNESCO that May 16th is the annual “International Day of Light”, it is clear that the world is taking notice of light, photonics, lasers, renewable energy, biotheranostics, and more. Thus, it bears remembering that light is not only at the beginning of everything, but has the power to both nurture and kill. High energy radiation has in a sense brought ‘us’ to where we are in ‘driving’ evolution; however, this also presents a constant danger in terms of photomutations. Light is a crucial effector in many biological processes ranging from photosynthesis and vision, to phototropism and signaling, to name but a few. Light can also heal, as pointed out by Herodotus more than 2.5 millennia ago with his description of heliotherapy. Next to the healing effects of light alone, it can also be used as an activator of pro-drug–drug conversions in photomedicine. Classic examples are the photosensitized generation of reactive oxygen species (ROS) to combat malignant cells and tissue (photodynamic therapy, PDT)1 and for the photodynamic inactivation (PDI) of microbes.2

The latter is of significant interest as antibiotic resistance,3 the rise of new infections, the current security situation (with respect to bioterrorism, recurring military and disaster scenarios), as well as food safety4 require the development of new strategies to combat bacterial and viral infections (Fig. 1).


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Fig. 1 Targets, means, and objectives of antiviral PDT.

As a result, recent years have seen a surge in studies on anti-microbial PDT,2 with most studies focused on antibacterial3,5 or antifungal PDT,6 and these areas have been reviewed extensively. This field is also often referred to as PACT (photodynamic antimicrobial chemotherapy).7 Here, we will focus exclusively on the area of antiviral applications.2,7–9,10,11 Similar to antibiotic resistance, resistance to antiviral drugs is also a current cause of concern.12 Thus, the photodynamic inactivation (PDI) of viruses is of interest as an alternative tool in antiviral treatments.8,9,10

The PDI of viruses can benefit from the same features relevant for PACT. The photodynamic mechanism rests on the light-induced formation of radicals, anions and, in general, ROS (via Type I and Type II mechanisms, see section 2) which damage the target cells or entities (e.g., bacteria, viruses, or more recently, prions).7–10,13 Though there are of course target structures for this damage (e.g., membrane structures of tumor cells and bacteria, lipid structures or proteins of the viral envelope, or nucleic acids) this effect does not rely on the specific interaction with a receptor. This ‘unspecificity’ of photodynamic damage is one of its advantages with respect to PACT or PDI. Given the genetic flexibility of viruses (and bacteria) this untargeted mechanism of action is less prone to trigger the development of resistance in the target entity.14 As resistance development is one of the main issues in fighting bacterial and viral infections, this makes PACT and PDI suitable to significantly contribute to the medical toolbox of fighting such infections and to overcome the increasing problem of antimicrobial resistance.

The photodynamic effect is only observed when light, a suitable photosensitizer (PS) and oxygen are present at the same time, hence photodynamic treatments are local treatments which usually limits their application to specific infection sites.14 Thus, PDI of viruses has clinically been applied mainly to localized viral lesions (e.g., herpes, warts – see later sections).15,16 However, in recent years systemic effects of photodynamic treatment triggering immune responses have been identified.17 This makes the PDI of viruses even more interesting as a complementary treatment option. In addition to treating viral lesions, PDI from the beginning offered potential in extracorporeal applications such as the disinfection of blood products (where it is now an accepted disinfection treatment – see later sections) or for laboratory viral safety measures.18

From a practical perspective one must note that there are now several PSs that have been approved for different medical treatments in patients, mostly for anticancer PDT.19 The available evidence on preclinical and clinical safety of PSs facilitates their investigation for potential new fields of application such as the PDI of viruses. Recent years have also seen significant advances with respect to PS formulation development.20–22 Some well-known PSs are highly lipophilic compounds, which hampers their administration and clinical application. By now, many new formulations have been investigated and authorized for medical use for these lipophilic PSs, which will also aid the development of antiviral treatments based on PSs. Still, while there is certainly potential in antiviral PDT, additional facts should be considered due to the complexity of this issue:

• The strong interdependence between light and the immune system.23 Light alone can be used to treat viral infections.15a,24 On the other hand some PSs may, in the absence of light, efficiently act as antivirals (see also further examples throughout).25

• The incidence of virus infection and cancer induction are sometimes connected, hence anticancer PDT may have antiviral PDI components as well. PDT is employed in (pre-)cancerous lesions induced by viruses, treating these cells with PDT can also reduce the virus load.26–28 Indeed, PDT is often investigated for the treatment of pre-cancerous and cancerous lesions in the genital region.27c,d,e,f On the other hand, early antiviral PDI treatments of warts pointed at the risk of malignancy development in treated cells.9

• Photoinactivated viruses can still trigger an immune response, which may be unwanted but is also useful with respect to a competent immune response and vaccination.18d,e,29

• Some studies have reported a reactivation of viruses (e.g., herpes simplex virus, HSV) by photodynamic treatments and viral inflammation as a side effect of PDT.30 Treatment of cells with PSs has been shown to facilitate the infection with adenoviruses via a photochemical internalization mechanism.31

Another aspect of photodynamic action and viruses, outside of the scope of this review but currently attracting considerable interest, is the ‘synergistic’ combination of viruses/viral components and PDT. This entails the use of viral particles or components as targeting units (e.g., peptides) or carrier systems (e.g., virus capsids) in combination with PDT to treat tumors or bacteria.32–34 PDT has also been used to augment the efficacy of oncolytic vaccinia viruses in metastatic tumors in vivo.35 Analogously, PDT can be combined with the phage therapy of antibiotic resistant bacteria36 and photochemical internalization (PCI)37 has been combined with virus particles for virus transduction.31

In this review we intend to outline the state-of-the-art in the field of antiviral PDI by highlighting developments in medicinal chemistry, current viral targets and clinical applications, PS design and translational aspects. Even with this limitation the literature is already extensive with about 4000 publications to-date dealing with dyes and photoinactivation of viruses. Of these, over 1300 cover antiviral photodynamic effects and formed the starting point for our analysis.38 The field is ripe for critical treatment in a monography, but that is outside of the scope of this contribution. Here, we focus on the various chemical classes of PSs, covering the medicinal chemistry thereof mainly for the past 10 years [2008–2018], and reviewing clinical and practical applications. We hope that a focus on the last decade will also serve to identify more clearly current trends in the PDI of viruses.

The literature basis for the current review were multiple searches in the CAS database with the respective search terms and combinations thereof, e.g., ‘photodynamic therapy’, ‘antiviral’, ‘photoinactivation’, amended by specific searches for photoinactivation of viruses within the main PS compound classes (vide infra). Though this review focuses on photoactive compounds which exert their action via ROS (PSs), some compounds relying on a different phototoxic action mechanism – notably psoralens39 – have also been included due to their clinical relevance. For the current review we chose an arrangement according to compound classes rather than virus targets, as the specific viruses studied in PDI investigations have often been chosen with respect to laboratory manageability (i.e., model viruses) rather than direct medical relevance. Current developments with respect to medical applications of the PDI of viruses are included as well in the respective chemical sections, as the clinical application of PSs largely depends on their regulatory status, i.e., clinical studies in PDI are mostly confined to specific PSs with an existing authorized indication such as antitumor PDT [e.g., δ-aminolevulinic acid (ALA) and haematoporphyrin derivative (see later sections)].

1.2 Historical development

The historical development of the medicinal use of dyes40 and PDT is well documented and has been the subject of several excellent treatises.41 Thus, the story needs no retelling, although “what's past is prologue”.42 Yet, it must be emphasized – in the context of the many contemporary publications in this area selling this as a ‘new’ concept – that the discovery of phototherapy and PDI stands at the historical beginning of the entire PDT field, going back about 130 years.

Finsen's landmark treatment of Lupus vulgaris43 is due to the photodynamic killing of Mycobacterium tuberculosis, probably via UV-A photosensitization of coproporphyrin III within the bacteria.44 The effects of PS accumulation in humans were noted about the same time by Prime, who, during attempts to treat epilepsy, noted that oral administration of eosin resulted in severe erythema in sunlight-exposed skin.41f,45–47 Raab and von Tappeiner's discovery in 1900, while attempting to develop antimalarials, that an external acridine dye upon light irradiation kills Paramecium caudatum presents the crucial experiment linking the photosensitizing effect of a dye and light.48 The requirement for oxygen, the third component of the PDT triad, was proven shortly thereafter by Ledoux-Lebards,49 Straub,46a von Tappeiner and Jodlbauer.50 These studies set the stage for all that followed in photodynamic therapy and even included what today we would call ‘translational medicine’, with Jesionek and von Tappeiner's treatment of a skin cancer with white light and topical eosin.51 After that period, interest in PDT waned and it took more than half a century for studies on light-activated antiviral compounds52 to begin in earnest, aided by the technological development of lasers.53 The 1960s saw a flurry of reports on photo-induced antiviral effects of simple dyes such as methylene blue and other phenothiazine derivatives, acridine orange, among others. Viral study objects included, but were not limited to, arbovirus, SV40, poliovirus, encephalitis virus, phages, and HSV.54 This period saw its ups and downs, e.g., when a report on HSV inactivation55a resulted in controversy as it was shown that it putatively retained its oncogenicity after treatment with neutral red.55 Clinical applications of PDI remained controversial for a time and over half of the aforementioned 1300 publications were published in the last decade indicating that, despite its long history, this is still a young and rapidly evolving field.

2. Mechanisms and targets for viral PDI

Past reviews7a,9,40,56 and the more recent ones3,8,10 have aptly described prior developments of the fields and the basic characteristics such as viral targets, photochemical mechanisms, and reactivity profiles. The fundamental mechanism of action of any PDT has three basic components irrespective of whether it is directed against tumor tissue, bacteria, viruses or other biological targets: a PS, light, and oxygen.1,13,19a,b,57–59 The photochemical processes behind PDT start with the excitation of the PS with light of a suitable wavelength corresponding to the absorption spectrum of the PS (Fig. 2). Irradiation results in the formation of an excited singlet state of the PS, e.g., the S1 state. Upon irradiation with white light or sunlight, as employed in daylight PDT,60 simultaneous excitation to the S1 and higher singlet states occurs. Usually very rapid, faster than any other process, relaxation from these higher excited singlet states to the S1 state occurs (Kasha's rule). From the S1 state the molecule can either return to the ground state by emission of a photon (fluorescence) or by radiationless relaxation via internal conversion; or the molecule can, via spin inversion (intersystem crossing, ISC), form an excited triplet state, T1. The return to the ground state is spin-forbidden which renders this T1 state longer-lived. The molecule can now again return to the ground state via photon emission (phosphorescence) or radiationless decay via internal conversion. Most importantly, this T1 state exists long enough to allow reactions with neighboring molecules, which are the ones relevant for PDT.
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Fig. 2 Modified Jablonski diagram. Processes relevant for the formation of ROS and subsequent oxidative damage are depicted in red.

Two different follow-up reactions are possible: the first being that the molecule in the T1 state can transfer an electron to other substrates (Type I photoreaction), e.g., biomolecules, which gives rise to the formation of radicals – most prominently the superoxide anion radical (Fig. 3).61,62 This can be converted to the much more cytotoxic hydrogen peroxide either enzymatically or through protonation. The superoxide anion radical can also reduce Fe3+ in cells to form Fe2+ and hydrogen peroxide, and in a second step Fe2+ can cleave hydrogen peroxide giving rise to highly reactive and cytotoxic hydroxyl radicals (Haber–Weiss/Fenton reaction). A possible direct charge transfer to oxygen plays only a minor role in this Type I photosensitization.62


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Fig. 3 Type I photoreactions. Reactions forming the main cytotoxic agents hydrogen peroxide and hydroxyl radicals, are depicted in red.

Alternatively, the molecule can react in an energy transfer process with molecular oxygen whose ground state is a triplet state (Type II photoreaction) (Fig. 2). Thereby the PS returns to the ground state (S1) while at the same time giving rise to the formation of singlet oxygen (1O2).63 Notably, in Type II photoreactions the PS molecule can now be excited again, undergoing the same sequence and generating more 1O2. Thus, both reactions give rise to the formation of ROS which are the actual toxic agents, and both are of course also involved in the PDI of viruses, as has been shown in multiple publications (see later sections).8,10

Many molecules can undergo this basic photochemistry,13,57,64 though not all of these are suitable as PSs. Firstly, this depends on the probabilities (quantum yields) of the different processes, thus high quantum yields for singlet excitation, ISC, and energy transfer to (triplet) oxygen are needed for an effective Type II photoreaction. However, other parameters are important as well; e.g., effective generation of 1O2 requires a suitable concentration of oxygen at the reaction site. The relative importance of Type I vs. Type II photoreactions therefore also depends on the local availability of oxygen.10,65 In fact, continued irradiation under concurrent oxygen depletion due to PDT treatment of the tissue is probably one of the important factors relevant for the side effects observed in the PDT of tumors and intra-treatment detection of 1O2 could contribute to enhanced PDT efficacy.66–68 Hence, determining oxygen consumption and tissue oxygenation is an important issue in PDT66 and considerable progress has been made recently with in vitro measurement of 1O2 in living cells and tissue.68,69 The question of oxygen consumption is directly connected to light dose and the light source. This has been extensively investigated for PDT70 and has also been the topic of studies related to the PDI of microrganisms.71–76

Equally important is the localization of the PS. Effective PDT requires a localization of the dye near sensitive molecular targets in order to exert a significant effect. This is due to the short lifetime of 1O2 in the biological environment. The decay has been shown to occur on a short μs time scale.65c The specific decay time depends on the localization of the PS, e.g., it has been determined to be 0.4 ± 0.2 μs in the vicinity of membranes in living cells,65a or 1.2 ± 0.3 μs in blood vessels in a recent in vivo investigation,65b but much longer times have also been found.65e The intracellular diffusion distance is small relative to the cell diameter which means the effect of 1O2 generated within a cell is spatially confined to its immediate surroundings. However, if generated near the cell membrane 1O2 may be able to cross the membrane. The lifetime for radicals generated via Type I photoreactions is considerably longer, but they, too, exert their action through reaction with sensitive molecular targets such as proteins or the double bonds in unsaturated lipids. It is known in the PDT of tumors that amphiphilic/slightly lipophilic PSs are more effective than readily water-soluble ones. This is due to a preferred localization of the former in membrane structures of the cells where they can do more harm to the cells than in an aqueous environment.77,78 On the other hand, PSs effective against (Gram-negative) bacteria are mostly (water-soluble) cationic compounds as these have a higher affinity to the bacterial membrane.79

Viruses have been estimated to be the most abundant and most diverse biological systems on earth.80 Typically their size ranges from 0.02 to 0.3 μm, though very large viruses ranging up to 1 μm are known. Viruses depend on cells (plant, animal or bacterial cells) for their reproduction and are classified according to their genome and method of reproduction. They consist of a DNA or RNA (single or double stranded) core, an outer protein cover, and, in some virus classes, lipids. Diseases caused by viruses range from relatively harmless infections such as the common cold (caused by Corona viruses) or diarrhea and gastroenteritis (caused by, e.g., Rota- and Adenoviruses) to serious diseases such as AIDS (caused by immunodeficiency viruses), Ebola (Ebola virus), SARS (SARS coronavirus) or, very recently, the Zika infections (Zika virus). In addition, virus infections are a well-known cause of certain forms of cancer [caused, for example, by HPV (Human Papilloma virus) or the Epstein-Barr virus].26,27b,28a,b,c Viral infections are also a serious problem in animal welfare and animal breeding.81

Based on the basic structure of viruses there are three principal molecular targets for viral PDI and for the reaction with the generated ROS: nucleic acids (DNA or RNA), virus proteins and, if present, viral lipids (Fig. 4).8a,10 The latter present an additional target for ROS and hence, such viruses with lipids and/or a protein envelope, in general seem to be more sensitive to viral PDI than those without.82–84 As commented on by Costa et al.,10 there are no contemporary investigations specifically investigating the effect of PDI on viral lipids. This may in part be due to general difficulties related to lipid analysis.85 On the other hand, there is indirect evidence for the deleterious effect of ROS on viral lipids and from investigations in anticancer PDT.10,62,86


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Fig. 4 The targets of PDI of viruses: nucleic acids, proteins, and lipids.

In contrast, a significant body of information is available on the effect of ROS on viral nucleic acids and proteins as a result of PDI, and this has been reviewed extensively.10,62,87 Photodamage to virus structures occurs via Type I and Type II photoreactions. Both mechanisms can be active at the same time, their relative importance being dependent on the PS structure, its concentration and the concentration of oxygen.73,88,89 Thus, mechanistic investigations into the PDI of viruses are attempting to elucidate the contribution of the two mechanisms.8,10 Experimentally this is done by adding specific quenchers for (oxygen) radical species (e.g., glutathione, mannitol, dimethylurea or SOD)88,90,91 or for 1O2 (e.g., sodium azide, β-carotene, histidine, or 1,3-diphenylisobenzofuran).89,91,92 These quenching experiments unequivocally established the importance of both mechanisms in the PDI of viruses. Costa et al.,10 in their concise evaluation of the literature involving quenching experiments, concluded that 1O2 is the most relevant agent in the PDI of mammalian viruses, whereas radical species play a secondary role. For bacteriophages the results are more complex, though here also 1O2 appears to play a major role. In some cases both processes seem to be concurrently active; e.g., as was shown with the PDI of the T7 phage using glycosylated porphyrin PSs.91 However, the situation is complicated by the fact that the relative importance of Type I and Type II photoreactions depends on the PS structure, and very rarely has the effect of different quenchers been investigated using constant PS and virus type.73,88–91 One also has to keep in mind that there are additional oxygen-independent phototoxic mechanisms that can contribute to the virucidal activity in the PDI of viruses. This is especially prominent in the case of psoralens, which can generate 1O2 but can also, upon UV-A activation effects, crosslink to pyrimidine bases.18d,39,93

DNA and RNA of viruses can be efficiently damaged by PDI. While PS binding or intercalation to the nucleic acids is not always needed for efficient photosensitization, it is known that cationic compounds, such as methylene blue, can cross the outer cover of viruses and intercalate into their DNA/RNA.94 For cationic PSs, electrostatic interactions are supposed to allow direct PS-DNA/RNA interactions. In Type I photosensitized oxidation reactions with DNA and RNA bases, a key step is the addition of O2 to short-lived carbon-centered radicals which originate from transformations of the primarily formed radical cations.62 For Type II photosensitized oxidation reactions, [4 + 2]-, [2 + 2]-cycloadditions, and ‘ene’ reactions with 1O2 dominate.62 Such oxidative transformations destroy the DNA leading to fragmentation, single strand breaks, and cross-linking with proteins. Prevention of viral replication and reduction of infectivity following DNA damage by ROS has been shown.8,10,95,96 Specifically, guanine moieties 1 are susceptible to oxidative damage yielding 8-oxo-7,8-dihydroguanine 2 as one of the main products (Type I photosensitized oxidation) (Fig. 5).8,10,56,62


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Fig. 5 Guanine 1 and its oxidation product 2.

Though viral DNA and RNA can be targeted by PDI, one has to remember that such direct DNA/RNA interference also principally bears the potential of mutagenicity.11,97 Potential ramifications of this issue are exemplified by early clinical applications of PDI for the treatment of HPV infections, where in some patients the development of Bowen's disease after treatment was observed. Whether the PDI treatment was causative or not has been a subject of discussion in the literature.9

Some PSs (e.g., ALA, PpIX, HPD, vide infra) have a high affinity to proteins and lipids. Such PSs are used to target the outer structures of the virus, i.e., unsaturated lipids as well as envelope proteins.10,62,86,98 Virus proteins typically undergo structural modifications such as protein cross-linking. Particularly, the photooxidative damage occurs at oxidation-sensitive amino acids such as tryptophan, methionine, cysteine, histidine and tyrosine. In addition, direct interaction of the PS with virus proteins may influence protein folding and thus affect virus function.10,62

While the clinical interest in the PDI of viruses of course targets viruses relevant for human and animal health, bacteriophages (viruses replicating in bacteria) also play a notable role in the PDI of viruses. Bacteriophages are frequently used as models for evaluating potential PSs for antiviral phototherapy.90,91b,92,98,99 Among other features, they are non-pathogenic to humans, more efficient, and easier to handle.10 In addition, most bacteriophages are non-enveloped viruses, and as these are less susceptible to PDI, it can be considered that if a PS is active against them, it will also be active against enveloped viruses.10

As mentioned above, the PDI of viruses is characterized by a ‘multi-target’ mode of action – ROS being able to react with RNA/DNA, proteins and lipids alike. In some cases, e.g., when treating HPV manifestations (see below), the antiviral effect is associated with purposefully killing the host cell (i.e., eliminating the wart). However, there is also the possibility that PDI intervenes with specific stages of the viral life cycle.8a It is conceivable that viruses at different stages of the life cycle show different susceptibilities to PDI.8a This viral life cycle comprises the general stages of attachment of the virus to the host cell, penetration of the virus into the cell (fusion of cellular and viral membranes), uncoating of the viral RNA/DNA, replication of the viral genome, assembly of new virions from newly synthesized viral nucleic acids and proteins, and finally release of the new virions from the host cell.100,101,102 Elucidating the specific effects of antiviral PDI on the different stages of the viral life cycle is a difficult task. However, a number of studies uncovering such specific PDI interactions has appeared (see also the discussion for the specific compound classes below), mostly related to RNA/DNA and protein interaction. Quite a number of these studies are related to the first step of the viral life cycle. PDI damage to viral proteins, for example, is sometimes associated with an inhibition of virus-cell fusion as some proteins play an important role in the attachment of viruses to the host cell surface. Lenard et al. could show that hypericin, as well as Rose Bengal, (for the specific discussion of compound classes see below) was able to inhibit virus fusion for the vesicular stomatitis virus (VSV), influenza virus, and Sendai virus (all enveloped viruses) by effecting cross-linking of viral proteins.103 The damaging effect of PDI on viral proteins important for virus-cell fusion has also been demonstrated for specific phthalocyanines and HSV-1,87 as well as for other PS and viruses.98,104–108 Interestingly, for certain PS it could be shown that though proteins relevant for virus attachment are targeted, nevertheless the virus antigenicity is preserved, something desirable with respect to vaccination.105–107 For example, for 1-iodo-naphthyl azide (see below Fig. 19) evidence was found that this compound selectively blocks virus-cell fusion at the pore formation and expansion step, while maintaining the antigenicity.107 For HIV the inactivation of reverse transcriptase by a PS while maintaining the functional integrity of viral surface proteins has been demonstrated.109 Inhibition of the fusion step has also been described by lipid membrane targeting.110–112 As well, an activity of PDI in the later stages of the viral life cycle has been elucidated in some publications.10 For example, it was shown that PDI against HIV with ALA was not effective in the first infection phase.113 Also, for a phthalocyanine a specific activity on the VSV viral RNA-RNA/polymerase complex has been reported.10,114

The in vitro protocols employed for evaluating the efficacy of PSs for antiviral PDI differ largely in the literature depending on the virus target. This makes comparisons of the activity of different PSs difficult, also, as often – instead of the target virus – model viruses are used.8a,10,115 Moreover, all virus replication relies on host cell structures whereby those host cells also play an important role with respect to reliability and comparability of the assays.8a,10,116,117 In general, the in vitro methods employed for determining antiviral PDI efficacy correspond to those used for non-light-activated compounds, amended by light activation protocols. General overviews on methods for determining antiviral efficacy are available in the literature.116,118 A very comprehensive overview and compilation of the in vitro methods used for testing antivirals is given in the recent review by Rumlová and Ruml.118 Information on in vivo models for assessing the antiviral efficacy is also given in reviews15b,119 as well as in the discussion of the compound classes below.

3. Photosensitizers for viral PDI

3.1 Introduction

As previously described, the only (photo)chemical requirement for a compound to have potential photodynamic antiviral activity is its ability to generate ROS upon illumination. Thus, a wide range of chemically quite distinct classes of molecules have been evaluated for their use in PDI – ranging from plant extracts such as psoralen to early industrial dyes (recall the early use of eosin and acridine mentioned previously), other natural PSs, sensitizers used in other areas of PDT, synthetic compounds derived from medicinal chemistry QSAR projects, to fullerenes and carbon materials,120 metals and oxides, complex synthetic 1O2 generating and delivering molecular systems121 as well as products from the materials sciences.

The example of psoralens illustrates an important additional aspect: apart from a photodynamic mechanism involving ROS (superoxide anion, hydroxyl radicals, 1O2), psoralens also exert their phototoxic action on viruses via an oxygen-independent photochemical reaction.39 Hence, compounds capable of such oxygen-independent inactivation of viruses have further contributed to the vast range of compounds employed for the photoinactivation of viruses.

In the subsequent text, the compound classes have been arranged roughly with respect to the status of their practical (medical/clinical) application in the PDI of viruses. Thus, the starting point entails compound classes for which there are up to now mostly in vitro investigations related to the PDI of viruses. These comprise compounds which have long been known as PSs, such as curcumins or hypericin, but also metal oxides and derivatives, as well as fullerenes and carbon nanomaterials. This is followed by, presumably, the most manifold class of PS, the tetrapyrroles – which for a long time have (and continue to) played a decisive role in the clinical PDT of tumors. Among these, specifically ALA and haematoporphyrin derivative (HPD) have progressed to clinical applications, mainly against different HPV manifestations.

Perhaps the area in which the PDI of viruses is most routinely used is the decontamination of blood products. Here, three main compounds and their derivatives are used: riboflavin, psoralen and methylene blue, which are reviewed consecutively. This is followed by an ‘outlook’ section on other PSs which have found interest in the PDI of viruses. Among them are compounds which were found to be potent antivirals and only at a closer look turned out to be PSs. With their different structures and approaches they provide further insight into the complexity of the field.

3.2 Curcumins

Curcumin (3), a polyphenolic compound isolated from turmeric, has been shown to exhibit a wide range of activities against various viruses122 and has been used as a photocytotoxic agent.123 However, due to poor bioavailability and significant reported metabolization, analogues to increase cellular uptake and absorption are desired for application in standard PDT.124 De Clercq et al. designed bioconjugates with a view to improving the bioavailability of curcumin, and did so via functionalization of the phenolic groups (Fig. 6).125 Two such compounds, 4a and 4b, with increased lipophilicity through peptide and fatty acid moieties, gave enhanced cellular uptake and these compounds also showed good results against VSV (4a) and both feline corona (FVC) and feline herpes viruses (FHV) (4b). A related compound 4c, containing folic acid moieties, was found to be very active against HPV.
image file: c9pp00211a-f6.tif
Fig. 6 Curcumin and selected bioconjugates.

Other studies have also investigated the potential antiviral activity of curcumin against HPV associated cells.126 Curcumin was cytotoxic against HeLa, SiHa and C33A cells, with a 57% and 63% reduction in viable cells on exposure to 60 μM of curcumin, to the former two cell lines, respectively. In addition to curcumin-induced apoptosis, selective inhibition of the expression of viral oncogenes E6 and E7 was observed, as well as downregulated COX-2 expression, a gene regulated by NF-κB.126a Finally, binding of AP-1, inherent to epithelial tissue-specific gene expression of HPV, was also selectively downregulated by curcumin.126 The results provided very positive data for the use of curcumin in the treatment of HPV for novel cervical cancer treatments.

As it was observed to be a strong inhibitor of NF-κB signaling, it was postulated that curcumin may exhibit anti-viral activity against influenza A virus (IAV) propagation.127 Indeed, treatment of MDCK cells with curcumin significantly reduced the viral titer at sub-cytotoxic doses (EC50 value of 0.47 μM), with less than 5% of mock-treated cells remaining. Moreover, the synthesis of viral proteins, such as haemagglutinin (HA) and neuraminidase was affected. The results indicated that the main target of curcumin is in the early stages of virus infection, most likely the attachment stage in the virus life-cycle. This was confirmed via a plaque reduction assay. The activity was deemed to be a result of interference of curcumin with viral binding to sialic acid receptors at the cell surface. A HA inhibition assay confirmed that curcumin inhibits HA in IAV.

Curcumin has also been demonstrated to be effective against norovirus (NV) surrogates. For example, it was applied as a PS against murine norovirus 1 (MNV-1) in oysters, leading to significant inhibition as well as damage to viral nucleic acids.128a Photodynamic action of blue-light activated curcumin against MNV-1 was investigated via plaque assay to measure the viral load. It was shown that the viral morphology was altered after photodynamic activation, suggesting a change in the viral capsid protein structures. To that end, curcumin as a PS was deemed to be both an efficient and cost-effective method of inactivating food-borne NV. Another study assessed curcumin activity against NV surrogates FCV and MNV.128b

An inhibitory effect on human immunodeficiency virus type 1 (HIV-1) was observed upon treatment with curcumin, via suppression of the viral long terminal repeat-directed gene expression, stimulated by tumor necrosis factor α (TNF).129 It was later demonstrated that curcumin exhibits anti-HIV-1 properties through diminishment of viral integrase and protease activities. HIV-1 integrase was inhibited by curcumin with an IC50 value of 40 μM, and results indicated interaction of curcumin with the integrase catalytic core. Energy minimization studies revealed that curcumin is able to fold back upon itself such that there is intramolecular stacking of the phenyl rings, bringing the hydroxyl moieties into close proximity within the active site.130 Inhibition of HIV-1 and HIV-2 proteases, with respective IC50 values of 6 and 5.5 μM, was also demonstrated for curcumin boron complexes such as 5.131 Results suggested that the boron component forces an orthogonal orientation leading to simultaneous occupation of two binding sites in the protease active sites. Work by Bahraoui et al. aimed to develop molecules that would interfere with Tat transactivation of HIV-1 long terminal repeat.132a Derivatives included a hydrogenated curcumin, to prevent the previously described folding and therefore stacking of the phenyl rings, a diether to investigate hydroxyl moiety activity, and a diester to enhance lipophilicity. A 70–85% inhibition of Tat transactivation was observed in HeLa cells upon activation of lacZ expression. Curcumin was also shown to inhibit the histone acetyltransferase activity of transcriptional coactivator proteins p300 and CREB-binding protein in vitro (IC50 = 25 μM), thereby suppressing acetylation of the HIV-Tat protein.132b

Kutluay et al. investigated whether curcumin could act as an anti-herpetic compound by blocking immediate-early gene expression in HSV133a and reported a significant reduction in immediate-early gene expression, as well as a reduction in HSV-1 infectivity in cell culture assays. A later study investigated the potential of gallium- and copper-curcumin derivatives, reporting good antiviral effects on HSV-1 in Vero cell line culture assays.133b In addition, the infectivity of HSV-2 virions was decreased upon exposure to curcumin prior to infection of HeLa cells.133c

Aqueous extracts of Curcuma longa Linn. against hepatitis B virus (HBV) in HepG cells repressed secretion of HBV surface antigens.134a Production of HBV particles was also suppressed, along with the level of intracellular HBV RNAs, indicating inhibition of replication. The anti-HBV activity was attributed to an enhanced cellular accumulation of p53 via transactivation of p53 transcription as well as increased p53 stability. It was later demonstrated that curcumin inhibited a lipogenic transcription factor, sterol regulatory element binding protein-1, thereby suppressing hepatitis C virus (HCV) gene replication via the PI3K/Akt pathway.134b It was also observed that a combination of curcumin and interferon (IFN) resulted in a synergistic inhibitory effect on HCV gene replication, with treatment highly efficacious when compared to that of IFN alone. Antiviral activity was also reported against coxsackievirus B3 (Cox B3) via reduction of viral RNA expression, protein synthesis and virus titer.134c A protective effect was observed on cells against virus-induced apoptosis and cytopathic activity, with analysis of different pathways establishing that curcumin inhibited virus replication through dysregulation of the ubiquitin-proteasome system. Another report investigated the antiviral activity of curcumin on a Neuro2a cell line infected with Japanese encephalitis virus (JEV)134d wherein a modulation of stress-related cellular protein levels, a decrease in cellular ROS levels and pro-apoptotic signaling molecules, as well as restoration of cellular membrane integrity was observed.

3.3 Perylenequinones

Perylenequinones comprise a range of natural products such as hypericin, hypocrellin and derivatives which exhibit distinct (photo)pharmacological activity.135
3.3.1 Hypericin. Hypericin (4,5,7,4′,5′,7′-hexahydroxy-2,2′-dimethylnaphthodianthrone, 6) is an anthraquinone derivative and one of the main active compounds in St John's wort (Hypericum perforatum L.) (Fig. 7).136–138 St John's wort is a traditional herbal medicine used mainly for the treatment of mild-to-moderate depression but also other indications such as bacterial infections and respiratory conditions,136,137,139 and is commercially available as standardized extracts, tea leaves, as well as oil infusions for topical use.137 With the exclusion of hypericin, St John's wort extracts contain a multitude of other components which also contribute to its pharmacodynamic effects, e.g., hyperforin (7), which plays an important role with respect to the drug-drug interactions observed with St John's wort.137,140
image file: c9pp00211a-f7.tif
Fig. 7 Hypericin 6 and hyperforin 7, and hypocrellins.

The photosensitizing action of hypericin has long been established;138 light-sensitivity is one of the well-known side effects of hypericin-based medicinal products and goes back to ancient times.137 There are numerous studies, including clinical trials, on the photodynamic action of hypericin and its derivatives against tumors; and also to a lesser extent against bacteria.136,141,142 Recent research has additionally focused on the light-independent pharmacodynamic effects of hypericin derivatives.142–144 Pronounced toxicity of hypericin against tumor cells in the absence of light has been reported and possible mechanisms are discussed in the literature.143,144 Hypericin has also been investigated for its antiviral properties.145 A notable review by Kubin et al. gives an overview on the different viruses and testing conditions employed for investigating these antiviral properties, both under light irradiation and light-independent conditions.146 Hypericin has been found to inhibit viral infectivity for a number of different viruses (e.g., HSV, HIV, IAV and VSV); for several viruses a light-independent antiviral activity has been observed.146 Earlier investigations looked at the utility of hypericin for the inactivation of infectious viruses in red blood cells.147

Based on promising in vitro results two phase I clinical trials were performed in 1999 and 2001, one in HIV-infected patients and the other in patients with HCV.148,149 The phase I dose escalation study in patients with chronic HCV infection was set to determine the safety and (light-independent) antiviral activity of hypericin. Pharmacokinetics showed a long elimination half-life for the two doses (0.05 and 0.1 mg kg−1) studied, with mean values of 36.1 and 33.8 h, respectively. The main side effect was phototoxicity, no anti-hepatitis C activity was detected.149 In the other phase I dose escalation study (0.25 or 0.5 mg kg−1) of HIV infected patients, cutaneous phototoxicity was so severe that dose escalation could not be completed, and no anti-retroviral activity could be observed.148

The antiviral phototoxicity of hypericin and its derivatives has been shown to depend on (light and) oxygen.150 Hypericin is able to generate 1O2 and other ROS,136,145,146 underlining its role as a classical PS. However, it has also been discussed whether a release of protons from hypericin upon irradiation, leading to a photogenerated pH drop, contributes to its antiviral properties, as enveloped viruses often depend on specific pH conditions during their life cycle.151 On the other hand, the PDT effect of hypericin is attenuated by endogenous proteins such as gluthathione-S-transferase.152

3.3.2 Hypocrellins and related compounds. Hypocrellins such as hypocrellin A (8) and B (9), are structurally related to hypericin and were isolated from the Chinese medicinal fungus Hypocrella bambuase, possessing both photodynamic anticancer and antiviral activities.136b,153 Similar to hypericin, efforts are under way to advance chemical functionalization and nanoformulation methods,154 and to improve possible biotechnological production of such compounds.155

Given the structural variability of hypericin and related compounds, and the variety of these compounds occurring in nature, there is an ongoing search for photoactive compounds based on this skeleton,135,136,156,157 including clinical investigations with new promising structures.158

3.4 Metal oxides and other inorganic materials

The inorganic Material Sciences have not stood back in the fight against viruses. Recent developments and potential applications of metal derivatives, notably oxides, are increasingly described in reviews.8,159 Potent virucidal activity has been reported for numerous metal complexes and metal oxides. An early study by Smith et al. examined a series of platinum pyridine complexes and their activities against various viruses.160 The tridentate 2,2′-dihydroxyazobenzene and 2-salicylideneaminophenol derivatives were shown to exhibit virucidal activity against enveloped viruses; equine infectious anemia virus (EIAV), HIV-1 and HSV-1. All experiments were carried out using ordinary laboratory light with an irradiation time of 30 min, and viruses were shown to be completely inactivated at concentrations as low as 1 μg mL−1 in solution.

Park et al. investigated the mechanism and efficiency of MNV-1 inactivation using TiO2 on solidified agar matrix.161 UV-C light was found to be the most effective in reducing viral titers, with negligible levels remaining after a 5 min treatment. It was observed that the hydroxyl radicals produced upon light irradiation were responsible for MNV-1 inactivation, quantified using p-chlorobenzoic acid as a probe. The purpose of the study was to simulate blueberries and establish an effective method for reducing the risk of HNV infection in fresh produce, which was successfully demonstrated using the solidified agar matrix. TiO2-mediated photocatalytic decomposition,162 in principle, offers a practical means for antimicrobial treatment in conjunction with environmental remediation of pollutants,163 possibly using ultrasound activation.164 An even simpler approach to improve the photodynamic effect of many PSs is the addition of ‘inorganic salts’, e.g., azides and iodides. This approach, widely used by Hamblin's group in antibacterial studies,165 who “discovered that aPDI can be potentiated (up to 6 logs of extra killing)”,165a offers a very straightforward and simple (in terms of regulatory affairs) means for PS improvement.

The virucidal activity of up-conversion nanoparticles (UCNPs) was demonstrated by Chu et al., with significant results obtained both in suspension and a murine model.166 This UCNP-based PDI strategy was envisaged to overcome common problems with current PDT approaches, such as PS hydrophobicity, poor target specificity and limited tissue penetration. Near infrared (NIR)-to-visible UCNPs consisting of NaYF4 nanocrystals were synthesized and co-doped with Yb3+ and Er3+ ions. The UCNPs were then coated with a layer of high molecular weight polyethyleneimine (PEI) to “solubilize” the non-polar UCNP core, and (phthalocyaninato)zinc(II) (ZnPc, the PS) molecules were physically adsorbed to the surface. On irradiation at 980 nm, the material emitted visible light, absorbed by the PS which converted nearby molecular O2 to ROS, resulting in viral inactivation. The Dengue virus serotype 2 (DENV2, New Guinea C strain) was chosen and the IC50 was determined to be between 4.4 and 44 μg mL−1 in suspension. The in vivo study gave promising results, with 100% of the suckling mice surviving to the final day of observation upon treatment with 440 μg mL−1 of ZnPc-UCNPs. To investigate target specificity, the ZnPc-UCNPs were conjugated with an antibody specific for the DENV2 envelope protein. The immunofluorescence assay revealed specific localization onto virus-infected cells only. The study also investigated virucidal activity against the non-enveloped virus, AdV5, and achieved significant reduction in viral titer.

Dragnea et al. described the incorporation of CdSe/ZnS semi-conductor quantum dots (QDs) into viral particles.34d,e The QDs were assembled inside the capsids of brome mosaic virus, a simple icosahedral virus. The result was a virus-like particle of similar size to the native virus, using easily manipulated PEG coatings to facilitate future industrial applications.

3.5 Fullerenes and carbon materials

Fullerenes and other carbon materials such as carbon nanotubes or, more recently, graphene have been envisioned for many biological and medical applications (Fig. 8).99,100 The antiviral potential of Buckminster's fullerene (C60, 10) and its derivatives was shown by Friedman et al. by inhibiting HIV-1 protease – in the absence of light.167 A few years later the photodynamic antiviral activity of C60 was demonstrated.83 PDT with fullerenes has been reviewed by a number of authors168 and their possible role in photodynamic viral inactivation has been addressed as well.8
image file: c9pp00211a-f8.tif
Fig. 8 Carbon materials used as PSs.

Fullerenes and their derivatives have been tested against a number of viruses such as Semliki Forest virus (SFV), VSV, HSV-1, HIV-1, mosquito iridovirus (MIV) and IAV, and the phage MS2.83,90 With respect to their photophysical features, fullerenes are characterized by the formation of long lived triplet states, the ability to generate 1O2 and other ROS, as well as a high resistance to photo-degradation.8a,168b,c,169 These properties render them suitable as PSs. Interestingly, fullerenes exhibit Type I as well as Type II photochemical reactions which is in contrast to, for e.g., tetrapyrrole PSs which in general predominantly undergo Type II photochemistry.57,168c,170 However, due to their hydrophobic nature and thus low solubility in polar solvents, fullerenes pose problems for biological and medical applications, and significant work has been invested in their functionalization to find suitable formulations.99c In some cases, C60 has been used in the form of aqueous suspensions83,171 or it has been formulated with polymers such as mPEG or polyvinylpyrrolidone (PVP).152 Alternatively, C60 can be functionalized with moieties enhancing solubility in polar solvents,172–174e.g., as polyhydroxylated92,175 or cationic derivatives.176,177 In particular, cationic derivatives such as fullerenes with three N-methyl pyrrolidinium groups exhibited high antiviral activity under irradiation.177

A study by Tanimoto et al. demonstrated that HIV-1 protease photo-degradation by compound 11 (Fig. 8) could be significantly enhanced by preparing the glyco-substituted derivative 12, which still showed low solubility. Thus, preparation of 13 with two additional carboxyl groups became necessary to increase the solubility in aqueous media.178 This compound effectively degraded HIV-1 protease under photoirradiation and was able to inhibit HIV-1 replication in living cells.

Granted, the low aqueous solubility of fullerenes can also be used as an advantage to exploit them as photoactive materials which can be easily removed from biological media after use. For example, aggregates of C60 have been used against HSV-1,179a and both C60 and C70 have been loaded onto silica.179b,180 Recently, C70 and silver have been loaded onto polymer NPs in order to obtain a dual functionality against viruses and bacteria. The respective nanocomposites were successfully tested in the synergistic inactivation of a model virus (bacteriophage PR772) and Escherichia coli.181a In this context it should be noted that fullerenes can also be used as scaffolds for the design of carrier systems for other PSs, e.g., porphyrins.181b Such fullerene based carrier systems for PS have been tested in vitro for their PDT activity against tumor cells.181b,c,d

There have also been a few reports on the use of graphene materials. Hu et al. used a graphene oxide-aptamer conjugate to target the phage MS2 as a model virus,182 while Akhavan et al. showed that photoirradiation of graphene-tungsten oxide composites resulted in protein destruction and RNA efflux in MS2.183 It should be mentioned that graphene materials bear potential not only for PDI of viruses but also for deactivation of viruses via alternative mechanisms, e.g., via selective binding. Deokar et al. recently synthesized sulfonated magnetic NPs functionalized with graphene oxide. This nano-construct exhibited a high antiviral activity against HSV-1 via photothermal destruction.184 Likewise, polyglycerol sulfate-functionalized graphene sheets were shown to selectively bind and thus inhibit the African swine fever virus, one of the most dangerous pig diseases and critical for livestock breeding.185

Similar to other compounds used for PDI of viruses, it should be kept in mind that such compounds may have antiviral properties in the absence of light also (e.g., fullerenes167,175). Therefore, substantial control experiments are necessary to elucidate the mechanism of antiviral activity as well as the oxygen dependence of virus photoinactivation, and the presence of oxidized species following virus inactivation has been investigated in many studies83,172,176a,182,183 and is also discussed in respective reviews.168

3.6 Porphyrins and porphyrinoids

Porphyrins and porphyrinoids (compounds with alterations to the porphyrin skeleton) are perhaps the most prominent class of PSs since the famous experiment of Meyer-Betz in 1913, when he injected himself with a derivative of haematoporphyrin.46b Since then virtually any class of porphyrinoids has been tested for their photodynamic properties. Apart from porphyrins 15, this also includes chlorins 16, bacteriochlorins 17, corroles 18, phthalocyanines 19 (Fig. 9) and others.13,19a,64,186–191 Many of these have also been investigated for the PDI of viruses. Porphyrinoids also dominate the PSs authorized for clinical use in PDT, such as ALA (as the precursor of protoporphyrin IX, vide infra),19a,187,192 haematoporphyrin derivative (HPD) and its congener Porfimer sodium,19a,187 Temoporfin,19a,187,193 or Verteporfin (the latter being mainly applied in the photodynamic treatment of age-related macular degeneration).19a,187,194
image file: c9pp00211a-f9.tif
Fig. 9 Main classes of porphyrinoids employed in the PDI of viruses.
3.6.1 Porphyrins. The PDI of viruses with porphyrin PSs has been reviewed as part of general reviews8a,9,10 as well as in specific reviews dealing with this compound class.195–198 Recent publications on synthetic porphyrins, as opposed to those derived or related to natural dyes, are mainly concerned with in vitro investigations on the PDI of viruses, whereas clinical studies have centered on PSs such as ALA or HPD.16c,26b,27b,199 This reflects the accumulated medical knowledge and regulatory status of the latter which have now been used in clinical practice for decades.13,19a,167
3.6.1.1 Synthetic porphyrins. Recent work on the PDI of viruses with porphyrins has focused on cationic porphyrin derivatives, specifically N-methylpyridyl-substituted compounds.75,89,98,200–208 Cationic porphyrins are well known to be effective in the PDI of bacteria as well as viruses.5,15,209–212

Costa et al. investigated the structure-activity relationship in a series of cationic porphyrins carrying two to four charges in the PDI of the T4-like sewage phage, a non-enveloped double stranded DNA virus.202a With the tri- and tetracationic porphyrins it was possible to reduce the phage to the limits of detection; however, the mono- and dicationic species did not yield a significant reduction of phage viability.202a The highest activity was observed for 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin tetraiodide (20) and 5-(pentafluorophenyl)-10,15,20-tris(N-methylpyridinium-4-yl)porphyrin triiodide (21) (Fig. 10). Interestingly, in the series of tricationic porphyrins (21 and 22), that with the polar carboxylic acid-substituent was the least active, which may point to a higher activity of compounds with an amphiphilic substitution pattern, i.e., combining polar cationic and unipolar substituents such as pentafluorophenyl. High antiviral activities for tri- and tetracationic porphyrins were also observed in other investigations.200,201,212a Tomé et al. have compared a mono-galactosylated tricationic porphyrin to the corresponding neutral compound,200 in an extension of earlier work.213 They found both compounds to be active in the PDI of HSV-1; however, the viral inhibition was more dependent on photoactivation for the neutral rather than for the cationic compound, i.e., the cationic compound exhibited virus inhibition also in the absence of light.200


image file: c9pp00211a-f10.tif
Fig. 10 Selection of structures used in the QSAR study on the antiviral activity of N-methylpyridyl-substituted porphyrins by Costa et al.202a

Costa et al. have subsequently used compounds 20 and 21 in more detail in several related publications,75,89,203,204,205 using the T4-like sewage phage as a model, as well as other phages. PDI of phage T4 with these porphyrins was shown to be dependent on the light source, fluence rate and total light dose with phage activation being more effective at lower fluence rates.75 In a comparative investigation of PDI with 5-(pentafluorophenyl)-10,15,20-tris(N-methylpyridinium-4-yl)porphyrin triiodide (21) in a series of DNA (T4-like sewage phage, phage of Aeromonas salmonicida, phage of Vibrio anguillarum, and the phage of Pseudomonas aeruginosa) and RNA (Qβ, phage MS2, phage LAIST_PG002) phages, compound 21 was able to inactivate all phages. However, the inactivation of the RNA phages required less time and lower PS concentrations than for DNA phages.204

The authors also investigated the mechanism of viral photoinactivation for the DNA-phage T4 and the RNA-phage Qβ.89 The protective effect of 1O2 quenchers (sodium azide and L-histidine) and of free radical scavengers (D-mannitol and L-cysteine) against PDI with the aforementioned cationic porphyrins was assessed in both phages. The 1O2 quenchers exerted a significant protective effect against PDI, thereby confirming a Type II photodynamic mechanism for the photoinactivation of the phages with these PSs. The protective effect was lower for the Qβ phage reflecting the higher sensitivity of RNA phages to PDI.89 Majiya et al. in a mechanistic approach investigated the PDI of the phage MS2 with 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin tetra-p-toluenesulfonate and identified the A-protein of the virus capsid as the primary target of photodynamic damage.98 That direct binding to viral DNA is not a prerequisite for efficient PDI was also determined in an investigation with the T7 phage using (N-methylpyridinium-4-yl)-substituted PS.201 In this case, free porphyrin was found to be more effective as a PS than DNA-bound porphyrin.181

Resistance formation has also been discussed as an issue for the photodynamic inactivation of bacteria and viruses.203,214 In a series of ten consecutive cycles of PDI against the T4-like bacteriophage with PS 21 no resistance formation was observed. This is in line with the ‘multi-target’ mode of action of PSs which lowers the probability of resistance formation.203

Vargas et al. tested the PDI of HIV-1 with a number of different metal complexes of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin.215 The HIV glycoprotein gp120 is known to interact with anionic porphyrins.216 The investigation identified distinct differences in the antiviral activity of metal complexes. Whereas there was no antiviral activity for the Cu(II), Ni(II), and Co(II) complexes, the PSs with Type I activity (Fe(III), Mn(II)) as well as those with Type II activity (Pd(II), Zn(II)), were effective in the PDI of HIV.215 Similarly, a comparative study of cationic and anionic PSs with bovine herpes virus (BoHV) type-1 indicated a higher activity for zinc(II) complexes.217 In a concurrent approach, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin has been loaded onto fullerene. This nanoparticle PS was effective in the PDI of HSV-1, the PS loaded on fullerene being more efficient than the free PS.218

More recently, some publications described antiviral materials.206,208,219 In this respect [5-(4-methoxycarbonylphenyl)-10,15,20-triphenylporphyrinato]platinum(II) was attached to nanoporous alumina membranes capable of inactivating VSV.219 Carpenter et al. have bound a tricationic (N-methylpyridinium-4-yl)-substituted porphyrin to cellulose paper on which PDI of influenza A, DENV and human AdV5 could be shown.206 In a similar approach from the same team, this porphyrin was embedded in polyacrylonitrile nanofibers and the material was photodynamically active against human AdV5 and VSV. The latter material gave a higher level of photodynamic inactivation compared to the cellulose-based materials, which was attributed to higher PS loading and a greater surface area in the case of the polyacrylonitrile nanofibers.208 Peddinti et al. reported bulk thermoplastic elastomer films containing ∼1 wt% (5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrinato)zinc(II) that were active against VSV (enveloped) and human AdV5 (non-enveloped).220


3.6.1.2 Naturally derived porphyrins – ALA and haematoporphyrin derivatives. More recent studies using naturally derived PSs employed ALA (23) and PpIX (24) (Fig. 11).8a,221,222 The use of ALA and its derivatives for the PDI of viruses has been covered by a number of general reviews that deal with PACT as well as other off-label applications for this compound.16c,27,199,222,223 The potential of ALA/PpIX for the PDI of viruses is long established224–229 and the work with this PS (precursor) benefits from the acquired clinical knowledge and also its regulatory status, as the compound is approved in the EU and the USA for treatment of actinic keratosis.230 These preconditions facilitate the use of ALA in other medical fields such as the PDI of viruses. Hence, most publications deal with related clinical applications of ALA and its derivatives.16c,27,222,223a
image file: c9pp00211a-f11.tif
Fig. 11 ALA and protoporphyrin IX.

Among these, due to the localized PDT treatment, the most common application is the treatment of different manifestations of HPV,24a,224,231–234e.g., acral233,235–242 and facial243,244,245 warts or warts in the genital region (Condylomata acuminata).219,246–257 In addition, antiviral PDT has been of interest in the treatment of recurrent respiratory papillomatosis.248 Apart from treatment, ALA can of course also be employed in the fluorescence diagnosis of HPV infections.246 For the most part, ALA has been employed, however methyl aminolevulinate (MAL) and hexaaminolevulinate (HAL) have been applied successfully as well.235,237 In the majority of these studies the efficiency of PDT for the treatment of viral warts has been demonstrated,233,235–238 though there are also studies in which only a moderate efficiency of PDT was observed.239

In a study by Fuchs et al. light alone (water-filtered infrared A) achieved a considerable effect.241 Successful treatment of warts with laser alone has also been reported by other authors.24a,d In a large randomized clinical trial (ALA-PDT as adjuvant treatment to CO2 laser) of Condylomata accuminata, the ALA-PDT treatment did not show additional benefits.256 A randomized trial with 80 patients comparing cryotherapy plus ALA-PDT and cryotherapy alone for the treatment of multiple Condylomata acuminata found the combination of cryotherapy and ALA-PDT to be more effective than cryotherapy alone.258 The evaluation of the ALA-PDT treatments of 531 patients showed an increase of the clearance rate with the number of PDT cycles. In addition, the clearance was higher for small lesions (ϕ < 5mm) than for larger lesions, and depended on the site of the lesion.259 In a comparative investigation of different methods to treat Condylomata acuminata with 361 patients the authors concluded that the treatment should be chosen according to the diameter of the lesion to be treated. For lesions with a diameter <0.5 cm ALA PDT is proposed, for lesions >2.0–4.0 cm cryotherapy or CO2 laser treatment followed by ALA treatment is recommended, and for lesions with a diameter 0.5–2.0 cm a combination of ALA-PDT and cryotherapy is suggested.250

Though more feasible for smaller lesions, the treatment of large Condylomata acuminata (Buschke–Löwenstein tumor) has been reported, too.260 In the cells ALA is transformed to PpIX, which is the active PS. The pharmacokinetics of PpIX after ALA administration has been followed in patients with urethral Condylomata acuminata, allowing determination of the optimal concentration and residence time for the ALA solution.251 Very recently it has been shown that the monitoring of HPV genotypes and viral loads in PDT treatment of Condylomata acuminata can help to optimize PDT treatment and can be indicative of PDT treatment efficacy.248c Likewise, the connection between ALA-PDT of Condylomata acuminata and the level of regulatory T cells, serum TGF-β1, and lymphotactin has been investigated, showing that low levels of serum TGF-β1 and lymphotactin played an important role in the occurrence and development of Condylomata acuminata.261 ALA, MAL or HAL are usually applied topically,235,237,239–241,243–245 though an intralesional injection has been successfully tested as well.236 The use of a high-pressure needle-free injection for this treatment has also been reported.262 Apart from Condylomata acuminata, ALA-PDT has successfully been used to treat the HPV-related Bowenoid papulosis.263

The most prominent side effect of the treatment of warts with PDT is pain;232,235,238,239,245,253 other reported side effects include erythema,238,239,245 exfoliation, and postinflammatory hyperpigmentation.245 Ulceration and photoonycholysis were observed in the case of intralesional injection of ALA.236 In addition, bacterial infections after ALA-PDT of Condylomata acuminata have been reported; these can be avoided by prophylactic topical antibiotics.264

PDI has also been used in the treatment of HPV in immunosuppressed patients.244,265 Due to the reduced immune status HPV can more easily spread, on the other hand a control of warts is specifically important in this patient group as certain types of HPV can be a source of neoplastic lesions.266 Xu et al. compared the efficacy between CO2-laser treatment alone and the combination of CO2-laser and PDT for the treatment of Condylomata acuminata finding the highest efficiency in the combination of both,247 as also observed by Šmucler et al. for the treatment of Verruca vulgares.24a

An important field of application for ALA and its derivatives MAL and HAL is also the treatment of HPV-induced (pre-)cancerous lesions, or of high-risk HPV infections.27,267–272 In a recent study by Chang et al., patients with persistent high-risk HPV infection were treated with topical ALA-PDT, with remission rates of 64% observed.269b While in this case the primary targets are the (pre-)cancerous lesions, there is also an effect on the virus load by the PDT treatment.27b,270,271 Apart from the treatment of HPV there have also been investigations on the PDI of other viruses such as HSV.15a,b,113

Very recently, it was shown that heme, Co- and Sn-PpIX can inactivate Zika, Chikungunya and other arboviruses by targeting the viral envelope. Interestingly, all three porphyrins showed a light-independent antiviral activity; however, the antiviral activity of Sn-PpIX could be enhanced with light irradiation.273 The same three porphyrins also showed a light-independent antiviral activity against yellow fever and the Dengue virus.274

Compared to ALA and its derivatives, recent years have seen fewer publications related to the PDI of viruses using haematoporphyrin derivatives.26b,275–278 Yin et al. investigated the PDI of bovine and human immunodeficiency virus with haematoporphyrin monomethyl ether (HMME). HMME successfully inhibited HIV in in vitro experiments. The antiviral effect could be quenched by both the 1O2 quencher sodium azide as well as by the hydroxyl radical scavenger D-mannitol.276 Like ALA, HPD has also been applied to cervical intraepithelial neoplasia.26b,277 In a nanoparticle-based approach targeted to develop ex vivo reusable antiviral agents Banerjee et al. have connected PpIX to multi-walled carbon nanotubes and showed that this conjugate was capable of reducing the infectivity of influenza A virus in mammalian cells.96

3.6.2 Chlorins. Chlorins (15) (and bacteriochlorins) have long been established as PSs for PDT,187,279,280 specifically because of their stronger absorption at higher wavelengths which renders them more effective PSs as a result of deeper tissue penetration.281,282 Apart from synthetic chlorin systems,281 chlorins derived from natural sources [modified chlorophyll derivatives such as chlorin e6 (31,3-didehydrorhodochIorin 15-acetic acid), 25 or phytochlorin, 26] play an important role as PSs,187,280,282 and their potential for the PDI of viruses have also long been known (Fig. 12).54
image file: c9pp00211a-f12.tif
Fig. 12 Chlorin type photosensitizers derived from natural sources.

Photoditazine, a water-soluble glucosamine derivative of chlorin e6 (27), has been used in an in vitro study against HSV to obtain a 1.5–2.5 log reduction of the virus titer.283 The same compound had earlier been shown to be effective in a cervical cancer model associated with HPV 16, a HPV type known to have a high probability of leading to neoplastic lesions.284

Another chlorin derivative, 3-phorbinepropanol-9,14-diethyl-4,8,13,18-tetramethyl-20-(3S-trans) (28) was tested on the Bovine viral diarrhea virus (BVDV, enveloped virus) and the encephalomyocarditis virus (EMCV, non-enveloped) in the context of blood sterilization.285 The chlorin was incorporated into liposomes which could then be immobilized on Sephacryl S-1000 beads. The enveloped BVDV was successfully inhibited in cell culture medium (4[thin space (1/6-em)]log); however, this inhibition significantly decreased when human blood plasma was used.

Temoporfin, a synthetic chlorin PS [5,10,15,20-tetrakis(m-hydroxyphenyl)chlorin, 29, Fig. 13], authorized in the European Union for the palliative treatment of head and neck cancer,193 has been tested in the treatment of anal intraepithelial neoplasia related to HPV; however, it proved to be only partially effective.286In vitro PDT with Temoporfin was also found to alter Epstein–Barr virus (EBV) microRNAs and LMP1 protein expression in nasopharyngeal carcinoma cells carrying EBV, shedding light on the complex processes involved in virus-induced oncogenesis by EBV.287 In a recent testing of a large cohort of medically active substances against the Zika virus, Temoporfin turned out to be one of the most effective. Notably, this effect was light-independent, suggesting that the compound itself may have antiviral properties against the Zika virus.25b


image file: c9pp00211a-f13.tif
Fig. 13 ‘Synthetic’ chlorin photosensitizers.

Recently, Latief et al. reported on the photodynamic inactivation of bacteria and viruses with the cationic chlorin PS “TONS 504” (30).76 This PS was tested in vitro against an HSV-1 and two acyclovir-resistant strains of HSV-1. Complete eradication of the HSV strains could be achieved at a concentration of 10 mg L−1 and a light energy of 10 to 30 J cm−2, and a concentration of 1 mg L−1 and a light energy of 20 or 30 J cm−2, respectively.

3.6.3 Phthalocyanines. As with the other tetrapyrrole derivatives, phthalocyanines (18) have been evaluated for the photodynamic inactivation of viruses, beginning with studies on the inactivation of viruses in blood in 1991.88,288 Their antiviral photodynamic activity has been discussed in general reviews on antiviral PDI.7–9 Phthalocyanines have been evaluated for the PDI of a large number of viruses, among them most prominently VSV, HSV, and HIV. They showed high activity against these and other enveloped viruses289–292 but were in general found not to be active against non-enveloped viruses,289,290,292 suggesting that the viral envelope is a main target of the ROS generated. However, the non-enveloped human rhinovirus type 5 (RV-5) was successfully photoinactivated with a sulfonated naphthabenzoporphyrazine.293 Simple tetrasubstituted phthalocyanines are conveniently accessible by tetramerization of the corresponding substituted phthalodinitriles, however this ease of synthesis is accompanied by the formation of all possible regioisomers during synthesis (cf., Fig. 14, 31 and 35a/b). The synthesis of specifically substituted compounds, such as the amphiphilic structures 32 and 34 (Fig. 14), requires different more sophisticated approaches.
image file: c9pp00211a-f14.tif
Fig. 14 Phthalocyanine photosensitizers.

Apart from their peripheral substituents the chemical and photophysical properties of phthalocyanines are also decisively determined by the central metal ion.291 For example, a higher PDI was found for a zinc tetracarboxyphthalocyanine compared to the aluminum derivative.291 In general, however, a clear tendency cannot be observed. The central metal ion of course influences the 1O2 quantum yield,290,291 which renders, e.g., zinc or aluminum phthalocyanines as attractive PSs. Rywkin et al. identified a Type II mechanism as the predominant one for the PDI of VSV with aluminum phthalocyanine tetrasulfonate (Fig. 14).88 On the other hand, metal phthalocyanines with lower 1O2 quantum yields may act via a Type I mechanism. Sobotta et al. observed infectivity reduction for several viruses such as HSV-1, para-influenza virus 3, Punta Toro virus, Sindbis virus, and IAV with copper phthalocyanines, for which they found a low 1O2 quantum yield.290 Nevertheless, most investigations have been made with (substituted) silicon, aluminum and zinc phthalocyanines.

With respect to peripheral substituents different functionalizations have been investigated, e.g., anionic (sulfonated), cationic, tert-butyl-, 1,4,7-trioxanonyl, and lysine-substituted compounds (generic structure 31, for specific examples see 32–35, Fig. 14), thereby also increasing the solubility of the phthalocyanines.289b,290 Sulfonated compounds were found to exhibit a higher activity against VSV and HSV than non-sulfonated derivatives.294a However, partially sulfonated compounds were more active than the tetrasulfonated derivatives for the N2 retrovirus and vaccinia virus.84 Allen et al. have tested this ‘amphiphilicity concept’ by introducing tert-butyl groups and combining them with sulfonation. Indeed, a higher activity for the more amphiphilic compounds was observed.84,294b High antiviral activities have been found for cationic phthalocyanines against, e.g., VSV, HIV-1, and the Sindbis virus;84,289a however, some of these compounds were also active in the absence of light.293,294 In a number of cases it has been shown that phthalocyanines can have an antiviral activity in the absence of light.295–298

Mostly, phthalocyanines have been investigated with respect to the antiviral PDI of blood products.84,88,288,294,299,300 One silicon phthalocyanine, “Pc4” (36), was specifically developed and investigated for this purpose, as it showed high activities against HIV and VSV,299,301 and was found to inactivate both cell-free HIV as well as actively replicating HIV and latently infected cells.301

Pc4 is also under investigation as a promising PS for tumor therapy.187 The primary targets of PDI of VSV with Pc4 were analyzed and a very rapid decrease in viral RNA synthesis following photodynamic treatment was observed.114 The phthalocyanine induced apoptosis in HIV infected cells.302 Experiments aimed at investigating in vitro the possibility of activation of the HIV promoter via a photodynamic treatment showed that Pc4 was unable to do so, while UV-A excited 8-methoxypsoralen was successful. A range of studies on phthalocyanines reported optimization of the irradiation protocol, with the aim of maintaining the virucidal activity while reducing treatment-induced damage to red blood cells.303–305 The photohaemolysis of human erythrocytes following photodynamic treatment with a ZnPc was analyzed by Zavodnik et al.306 The use of protective agents against such damage to red blood cells was also evaluated; e.g., employing a water-soluble vitamin E derivative or reduced glutathione. The latter was able to protect red blood cells from binding IgG following PDI with phthalocyanines.304,307 This IgG binding is critical, as it can interfere with cross-matching tests performed prior to transfusion.

In addition to blood product disinfection, phthalocyanines have been proposed and tested for the inactivation of adenoviral vectors in the context of biosafety in laboratories using recombinant adenovirus vectors gene transfer and gene therapy.308

A few publications have addressed the targets of antiviral PDI with phthalocyanines.87,309 For aluminum phthalocyanine tetrasulfonate it was elucidated by quenching experiments that 1O2 plays the dominant role for VSV inactivation.9 For the same compound, strong inhibition of viral RNA polymerase of VSV was detected after PDI; HPLC and electrochemical analysis detected the formation of 8-oxo-7,8-dihydroguanosine.114,300 For an amphiphilic phthalocyanine major changes in the protein profile of HSV-1 after PDI were observed; specifically for glycoprotein D, one of the structural proteins of HSV-1.87

Particle-based formulations containing phthalocyanine PSs have also been tested for antiviral PDI. Silica up-converting nanoparticles loaded with ZnPc have been used against the DENV.166,310 Recently, particle-based phthalocyanine PSs and cholinyl-substituted aluminum phthalocyanine loaded on silica gel were used for MS2 phage and poliovirus inactivation.311

3.7 Riboflavin

Riboflavin, or vitamin B2, (37, Fig. 15) is an essential vitamin in humans which generally acts as a co-factor for flavin coenzymes, playing an essential role in human cell metabolism.312 Its potential role in the photoinactivation of microorganisms has been known for over half a century.9,313
image file: c9pp00211a-f15.tif
Fig. 15 Riboflavin.

As it is a naturally occurring compound in the human body, this facilitates the use of riboflavin for medical applications. From the beginning, the application of riboflavin in PACT and the PDI of viruses which has found most interest, and is still the most intensely investigated field, is the decontamination of blood products.9,18b,314–316 Along with the psoralen derivative 4′-(4-amino-2-oxa)butyl-4,5′,8′-trimethylpsoralen (amotosalen) and the phenothiazinium dye methylene blue (cf., below), riboflavin is one of the three photoactive dyes in standard clinical use for pathogen reduction in blood products. An overview on the approval status is given in two recent reviews,18b,317 and there are numerous reviews detailing its application in blood decontamination.18b,93b,316–321 The fact that over 100 million units of blood donations are collected each year underlines the medical importance of PDI and PACT for blood products.317

Due to the extensive knowledge of this naturally occurring compound, riboflavin has been qualified by the FDA as GRAS (Generally Regarded as Safe).93b It binds to the nucleic acid bases of DNA and RNA, and upon UV-irradiation, specifically oxidizes the guanine bases in nucleic acids by a single electron transfer reaction.8,10,316,318a,322 In follow-up reactions, 1O2, hydrogen peroxide and hydroxyl radicals are formed.93b,316,318a This results in irreversible single strand breaks in nucleic acids, damaging the pathogens.316,318b,319 The primary photoproduct of riboflavin is lumichrome (38). Neither riboflavin nor its photoproducts need to be removed after treatment.93b Riboflavin has been shown to be effective against enveloped as well as a number of non-enveloped viruses – to include HIV, West Nile virus, VSV, IAV, porcine parvovirus, pseudorabies virus, human hepatitis A virus (HAV), encephalomyocarditis virus, Sindbis virus, the MERS coronavirus, among others.18b,316,320–324 Riboflavin is the active PS in the MIRASOL Pathogen Reduction Technology System (Terumo BCT, Lakewood, CO, USA),93b,325 which is used to treat platelet and plasma products.18b,93b,317,323 Moreover, it is also in use for pathogen reduction in whole blood.18b,316,317 Due to the strong absorption of visible and UV light by whole blood, methods suitable for other blood products are not simply transferable to whole blood (see section below on psoralens).316,317 Pre-clinical18b,323,326 and clinical studies18b,327 have been performed with riboflavin/UV-treated blood products to assess its safety and efficacy and an overview is given in recent reviews.18b,316,317,323,328

As for all blood inactivation techniques one major interest is of course how the blood preparations are affected by the treatment.18b,93b,316,317,320 For example, in a publication by Larrea et al. it was shown that, as also observed for other pathogen reduction procedures for plasma products, treatment with riboflavin and UV light reduced the activity levels of several pro-coagulant factors, whereas coagulation inhibitors were preserved.329 An investigation on the photochemical inactivation of HBV with methylene blue and riboflavin showed the photochemical inactivation of HBV with riboflavin, in contrast to methylene blue, resulted in the loss of ability to regulate viral immunity, and to be related to the different photochemical inactivation mechanisms.330 The riboflavin/UV treatment is able to inactivate residual donor leucocytes and T-cells.93b,326,331 Recently, a decrease in platelet function with storage time was observed and this correlated with a decrease in the effectiveness of transfusions.332

Proteomics are now used as a tool to assess the changes to the proteome associated with the different methods of pathogen inactivation during storage of platelet concentrates.316 Results have been summarized by Prudent et al. for a comparative evaluation on riboflavin/UV, amotosalen/UV-A, and UVC pathogen inactivation.333 For riboflavin this is amended by a very recent study on protein changes occurring upon Mirasol riboflavin/UV treatment.334 Semi-quantitative proteomics also emerged as a tool to differentiate between protein changes due to the riboflavin/UV treatment and the so-called platelet storage lesion.334 Consistent with oxidative damage, riboflavin/UV-treated platelets exhibited an increase in the formation of ROS by day five of storage, and the NF-κB signaling pathway was also found to be activated in the treated platelets.335

One rare, possible serious complication after transfusion is the transfusion-related acute lung injury (TRALI).336 In an in vivo study in BALB/c SCID mice it was shown that the riboflavin-treated whole blood did not produce lung injury after short storage. After longer storage development of a mild lung injury was observed; however, this was storage-dependent and was without significant differences to the control groups.337

3.8 Psoralens

Psoralen and its derivatives have long been known for their photosensitizing properties and for their potential application in the phototherapy of viruses.338 Psoralen is a heterocyclic, tricyclic compound consisting of a furan and a pyrone ring (39, Fig. 16). Psoralens have an affinity to DNA and RNA and intercalate in nucleic acids. Upon activation with UV-A, covalent crosslinking to pyrimidine bases occurs.18d,93 This results in the formation of mono- and di-adducts which are eventually responsible for the inactivation of viruses and bacteria.93b,314,315 Its mechanism of action is different to that of other PSs, and 8-methoxypsoralen (40) is known to have mutagenic potential.93 However, psoralens have also been found to generate 1O2, hence, this pathway also contributes to their phototoxic properties.39
image file: c9pp00211a-f16.tif
Fig. 16 Psoralen and derivatives.

With respect to the PDI of viruses, many different psoralen derivatives have been evaluated, in an attempt to maintain the antiviral and antibacterial potential while at the same time lowering mutagenic potential and toxicity.93b,339 From this research the compound 4′-(4-amino-2-oxa)butyl-4,5′,8′-trimethylpsoralen (Amotosalen, also S59, or AMT, 41) has emerged as a promising development.340

Compared to 8-methoxypsoralen, amotosalen is more hydrophilic because of its amino group. The compound is water-soluble and can more easily pass through cellular membranes. Moreover, under physiological conditions it is cationic and therefore has an increased affinity to DNA.93b,340b,341 Amotosalen is the active compound in the INTERCEPT Blood System (Cerus Corporation, Concord, CA, USA).340,342 Recent publications on the PDI of viruses with psoralen derivatives have centered around amotosalen and its use in the decontamination of blood products.18b,93b,316–321 As mentioned, amotosalen/UV-A treatment induces inter- and intra-strand crosslinking in nucleic acids, which is the mechanism responsible for the antiviral action. After the irradiation procedure, most of the amotosalen is photodegraded and a large portion consists of amotosalen dimers.93b,341,343 In the INTERCEPT process, these and other photoproducts, as well as remaining amotosalen in the treated blood products, are removed or at least reduced in a subsequent filtering step.316,341,343 The remaining amotosalen photoproducts were not found to induce neoantigen formation, lowering the probability of adverse immune responses.344

Amotosalen has proven to be active against a large number of both enveloped and non-enveloped viruses, i.e., HIV, HBV, human T-lymphotrophic virus type I and II, cytomegalovirus (cell-associated), BVDV, West Nile virus, Chikungunya virus, IAV, SARS Corona virus, DENV, Crimena-Congo hemorrhagic fever virus, Parvo virus B19, blue tongue virus, human AdV, the Zika virus, and others.18b,d,320,321,340b,345,346 For DENV inactivated with amotosalen/UV-A, an in vitro study showed that the inactivated viruses keep their immunogenicity, i.e., they provoked T-cell responses similar to that of non-inactivated viruses.346 Later it was shown that the same holds for other viruses, e.g., the Crimean-Congo hemorrhagic fever virus, Lassa virus, MERS virus and the Rift Valley Fever virus.18d

The development of the amotosalen-based blood disinfection approach involved a range of studies on the pre-clinical safety and clinical efficacy of the product. A concise overview is given in recent reviews.18b,320,340b A description of multi-center clinical trials can be found in the review by Schlenke,18b while the toxicology testing has been summarized by Dayan341 and others.18b,347 One issue in the safety-testing was of course genotoxicity. In this respect, a review on the genotoxic potential of the amotosalen/UV-A pathogen reduction technology and the assessment of the possible hazards in recipients of treated platelets concluded that the mutagenic hazard to recipients of treated platelets is negligible. Any observed genotoxic effect in the in vitro/in vivo tests at high concentrations could be attributed to residual amotosalen.347

The results from the two recent phase III trials on amotosalen-treated platelet products were published in 2010348 and 2011.349 The later study involved a randomized, controlled, double-blind trial to evaluate the efficacy and safety of amotosalen-treated platelet components stored for 6–7 days vs. conventional platelet components (non-inferiority design), and showed the non-inferiority of the amotosalen-treated platelets. In the former study a higher rate of adverse events (bleeding events) was found for the amotosalen-treated product. However, there has been some discussion in the literature about the evaluation of the bleeding events and the study design,18b,c,350 and this is also evaluated in a meta-analysis of all five main phase III studies.351 In a survey on the occurrence of adverse events with four types of fresh-frozen plasma in France (in the last 10 years), comprising two phototreatment methods (amotosalen/UV-A and methylene blue/light, vide infra) along with two other types (solvent-detergent316 and quarantine) all four types were found to be associated with low occurrences of adverse events (7.14–1.05 adverse events per 10[thin space (1/6-em)]000 deliveries).352 A low occurrence rate for adverse events with amotosalen/UV-A-treated blood products was also stated in two recent reviews taking into account data from post-marketing studies and a review based on application data in the USA.353 A recent retrospective analysis study with 306 patients in need of massive transfusion observed no negative effects on clinical outcomes, in-hospital mortality, and length of stay.354

One of the serious possible complications of transfusion is the graft-versus-host disease, which is caused by T lymphocytes of the donor. As photoinactivation techniques can inactivate proliferating T-cells, the use of blood components treated in this manner may be a measure to lower the risk of this complication. A recent review concludes that amotosalen/UV-A-treated blood products may indeed serve this purpose.355

The effects of amotosalen/UV-A on platelets and blood products have, of course, also been analyzed and summarized in a number of publications.333,340 These investigations hinted to a reduced platelet function following amotosalen/UV-A treatment and the mechanism for this has recently been investigated by Stivala et al.356 The authors concluded that the amotosalen/UV-A treatment induced platelet p38 activation, glycoprotein Ib shedding and eventually platelet apoptosis by a caspase-dependent mechanism. As a result, platelet function and survival are reduced. Thiele et al. compared the effects of amotosalen/UV-A treatment and gamma-irradiation by proteomics based on an LC-ESI-MS/MS analysis.357 It was found that gamma irradiation initially caused more alterations in the platelet proteome than amotosalen/UV-A. However, this effect was reversed after five days of storage. After this period there were more changes in the amotosalen/UV-A treated platelets, hinting at enhanced storage lesions in the amotosalen/UV-A treated platelets.

The amotosalen/UV-A procedure is not applicable in whole blood due to the color and strong absorption of the latter, which would require unacceptable high intensities of UV light. Hence, a method has been developed for whole blood that does not rely on photoinactivation, but acts via a bis-alkylating agent to crosslink nucleic acids.358 The compound amustaline [[N,N-bis(2-chloroethyl)]-2-aminoethyl-3-[(acridin-9-yl)amino]propionate dihydrochloride], an acridine 42 derivative, (43, Fig. 17) used in combination with glutathione, is currently in clinical development.314,315,327,358,359 This inactivation corresponds to other chemotherapeutic viral inactivation methods such as beta-propiolactone, which is commonly used for pathogen inactivation in vaccine preparations.360


image file: c9pp00211a-f17.tif
Fig. 17 Amustaline.

3.9 Phenothiazines and methylene blue

Phenothiazines (44) and among them the most prominent compound, methylene blue (45), are perhaps the best-known antibacterial and antiviral PSs (Fig. 18). Investigations on their antiviral activity date back to the beginning of the 20th century, with the observations of Oscar Raab48 and investigations in the 1920s.361,362 The antibacterial and antiviral activity of phenothiazinium PSs has been extensively reviewed, specifically for this compound class,56,362–365 and also as part of general reviews on pathogen inactivation.2,7a,8a,9–11 A large number of structural modifications on methylene blue and its congeners have been reported, including straightforward modifications as well as reactions, e.g., substituting sulfur with selenium thereby yielding selenoxanthylium PSs.366
image file: c9pp00211a-f18.tif
Fig. 18 Phenothiazines and photooxidation productions of methylene blue.

In the 1970s, phenothiazine derivatives were used to treat herpes infections; however, these trials were overshadowed by the occurrence of Bowen's disease in some patients which has been attributed to the interaction of the PS with viral DNA provoking oncogenic effects.9,362,367 That said, there are still examples of successful treatment of HSV using methylene blue.367f,g Later work has focused on the application of phenothiazine derivatives in the pathogen inactivation in blood products, with methylene blue as the lead compound.56,363,364 One reason for the prominent role of methylene blue is the acquired clinical evidence on its safety in humans after long term use in the treatment of methemoglobinemia.56 Today, methylene blue/white light is routinely used for blood product disinfection.93b,316,318,319,320,321 Introduced in 1991,18c the current approval status is given in recent reviews.18b,317 The methylene blue/light treatment is also one of the standard procedures mentioned in a WHO report on viral inactivation and removal from blood products.368

Nevertheless, though mainly used for blood product disinfection, recent clinical reports are related to the treatment of virus infections by methylene blue/light (vide infra).369 Methylene blue is known to bind to DNA, either to the outer helix or by intercalation, especially in guanine- and also cytosine-rich regions.8a,56,93b The dye is known to undergo Type I as well as Type II photoreactions.56,93b,364 Direct electron transfer is probable, leading to DNA strand breaks in the absence of oxygen or at low oxygen concentrations. In the presence of oxygen, photooxidations occur via a Type II mechanism; this has been proven by the formation of 8-hydroxyguanine in nucleic acids upon methylene blue phototreatment.56 The damage resulting from Type I and Type II photoreactions is not limited to DNA/RNA, as methylene blue also damages viral surface structures such as proteins. Methylene blue itself is degraded to partially demethylated products (Azure A and B), leukomethylene blue and thionine (46–49).93b When two RNA viruses, Sindbis virus and HCV were treated with methylene blue/light, followed by nucleic acid amplification to determine RNA lesions, the nucleic acid amplification of the treated viral RNA was found to be inhibited in a time-dependent manner.95 As the inhibition of RNA amplification for the Sindbis virus was to be directly correlated with a loss of in vitro infectivity, the authors concluded that RNA was the main target of methylene blue/light inactivation in this case.95

Because of its longstanding use as a PS, methylene blue has been effectively tested against a large number of viruses, overviews are given in the aforementioned reviews.56,362–365 This list is constantly expanding,370–372 in response to new medical needs as exemplified, e.g., with testing methylene blue/light for enterovirus 71 or Zika virus inactivation.370b,372 As mentioned above (section 3.7 riboflavin) it was shown that the immunogenicity of hepatitis B is retained after photochemical inactivation of HBV with methylene blue.29,330

Commercially, methylene blue is used as the active substance in the THERAFLEX MB Plasma system (Macopharma, Tourcoing, France).18c,373,374 An older similar method also using methylene blue is referred to as the ‘Springe method’.93b,373 Prior to the addition of methylene blue in the form of a dry pill, the plasma is filtered to reduce, among other things, the levels of remaining blood cells, intra-cellular viruses and microparticles. After illumination, a second filtration step has been introduced to reduce the residual amount of methylene blue and its photoproducts.93b,374b,375 The THERAFLEX MB procedure has been found to be active against enveloped as well as non-enveloped viruses such as HIV, West Nile virus, BVDV, pseudorabies virus, IAV, Sindbis virus, porcine parvovirus, porcine encephalomyocarditis virus, HCV, Zika virus, DENV and Chikungunya viruses.18b,370 The THERAFLEX MB system has been analyzed in a number of comparative reviews together with the MIRASOL (riboflavin) and the INTERCEPT (amotosalen) system.93b,316–321

The previously mentioned analysis by Bost et al.352 found methylene blue/light (as amotosalen) to be associated with only low occurrences of adverse events. In 2007, Politis et al. compared fresh-frozen, leuco-reduced plasma inactivated with methylene blue/light (THERAFLEX MB) to non-methylene-blue-treated plasma with respect to safety and efficacy after 5 years of clinical experience.376 The coagulation factor losses remained in the accepted range, the rate of occurrence of adverse reactions was lower in the methylene blue-treated plasma group (though the data basis for the untreated plasma was of course much broader), and no seroconversions for infectious diseases were reported for the methylene blue-treated plasma group.376 This safety profile was confirmed in a follow-up study in 2014.18c,377

In an in vitro study on the quality of methylene blue-treated plasma (THERAFLEX MB) stored for up to 27 months the authors measured coagulation-related parameters (i.e., several coagulation factors, inhibitors of proteins C and S, and antithrombin and activation markers).378 They observed a decrease in clotting factors which remained, however, in the range found for healthy subjects. The authors concluded on a safe storage period of 2 years.378 A subsequent study analyzed the recovery of factor VIII and fibrinogen from plasma samples obtained from whole blood and apheresis donations and treated with the THERAFLEX MB system.379 The mean factor VIII level after treatment exceeded 0.5 IU mL−1 in all series and varied between 78% and 89% in the different series. For factor VIII, the recovery was found to be dependent on plasma source. The mean levels of fibrinogen after treatment exceeded 200 mg dL−1 in all series, with the level of fibrinogen after treatment correlating with the level prior to treatment.379

A few years ago, the bacterial and viral reduction capacity of the THERAFLEX MB system was compared in a challenge study with a series of bacteria and viruses in lipaemic plasma.380 The authors concluded that the system was effective in bacterial reduction mainly because of the integrated filtration system, the remaining bacteria were effectively reduced by the methylene blue/light treatment. Viral reduction via the THERAFLEX MB system was able to effectively compensate for lipaemia.380 Last year, the same group investigated the effect of plasma temperature on viral inactivation capacity and plasma quality of methylene blue/light-treated plasma.381 They tested three temperatures (5, 22, and 30 °C) using three viruses (Suid herpes virus, BVDV and VSV). Viral inactivation was significantly decreased at 5 °C. At higher temperatures the photocatalytic degradation of methylene blue was increased.381

Though being in standard clinical use, there are doubts over the use of methylene blue/light-treated plasma for patients receiving multiple plasma donations, e.g., in the case of patients suffering from thrombotic thrombocytopenic purpura.18c,382 Moreover, there have been reports on severe allergic reactions following the administration of methylene blue/light-treated plasma.18c,383 As a result of these concerns and the evaluation of the data, the authorization for the THERAFLEX MB system was withdrawn in France in October 2011 by the health authorities.18c,352 Other evaluations did not find an increase in severe allergic reactions.18c,384 A position statement from the UK [Joint UKBTS/HPA Professional Advisory Committee/Serious Hazards of Transfusion (SHOT)] on the issue recommended no immediate withdrawal but a close, proactive monitoring of reaction rates to methylene blue/light-treated plasma.385 The company marketing THERAFLEX MB has also developed an alternative treatment method which does not make use of a photosensitizing agent, but relies on irradiation with UV-C to achieve pathogen reduction (THERAFLEX UV-C). The current clinical and regulatory status of this system has been summarized in recent reviews.18b,93b,317,352,370a,b,386 Results from a phase I study with this system for pathogen inactivation in platelet concentrates have been published.387

3.9 Other photosensitizers

Naturally, there is a variety of other organic PS structures for which investigations on the PDI of viruses have appeared in recent years, partly covered in the general reviews.8a,9,10 These include PSs that have long been known but are not so much in the current focus of the PDI of viruses, such as Rose Bengal (50),388,389 cyanine dyes390 or rhodamine B (51), and derivatives such as octadecyl rhodamine B (‘R18’, 52),112 as well as new structures (Fig. 19)105a,109,110 or multicomponent plant extracts.104 In the following section, a selection of contemporary studies and new approaches will be presented.
image file: c9pp00211a-f19.tif
Fig. 19 Examples of other compounds tested for the PDI of viruses.

One compound that has attracted considerable interest in the PDI of viruses is 1,5-iodo-naphthylazide (also referred to as INA, 53).106 INA is a photoinducible alkylating agent active against enveloped viruses.105 As a hydrophobic compound, INA is incorporated into the lipid bilayers of virus envelopes. When activated by light (UV-A) photoinduced alkylation of proteins in the lipid bilayer occurs.105–107

A few years ago, INA was also found to inactivate Encephalomyocarditis virus (EMCV), a non-enveloped virus.391a In this case, an association of INA with the viral RNA was observed. With its mechanism of action, INA was able to inactivate the virus but maintain its structural integrity and antigenicity, thus keeping its ability to provoke a competent immune response. Treatment of mice with INA/light-inactivated Zaire Ebola virus was found to protect the mice if they were subsequently challenged with an otherwise lethal dose of the untreated virus.106 The same was demonstrated for the Venezuelan equine encephalitis virus (VEEV).391b Viral inactivation, while maintaining virus structure and immunogenicity, has also been shown for preparations of the IAV and DENV.107,346

INA/UV-A and amotosalen/UV-A were compared in the inactivation of alpha and pox viruses, and both procedures effectively eliminated viral infectivity, though amotosalen proved to be more active than INA on vaccinia and pixuna viruses.392 Belanger et al. have studied the effect of different iodo- and azido-substituted naphthalenes and UV-A irradiation on HIV-1. For prolonged irradiation times (15 min, compared to 2 min) with the aryl azides they observed the additional effect of viral protein aggregation which they attribute to ROS formation based on photochemical conversion of the azido-substituted naphthalenes.105

Development and structural optimization of PSs obviously will always address the question of PS affinity to the intended target of PDT or PDI (tumor cells, bacteria, viruses). The other important aspect of optimization is the photophysical and photochemical part of PDT and PDI, i.e., the generation and release of 1O2 and other ROS. In anti-tumor PDT, a recent approach involves the ‘storage’ or retarded release of 1O2via the reversible formation of endoperoxides with suitable aromatic moieties,121e.g., with pyridone-appended porphyrins (54, Fig. 20).393 This ‘storage’ and thermal release of 1O2 has also been investigated for the PDI of viruses.394,395 Dewilde et al. used a water-soluble naphthalene derivative (55) to effectively inactivate the enveloped viruses HIV 1, HSV type 1, cytomegalovirus, and VSV, evidencing that 1O2 plays an important role in the inactivation of these viruses, as the thermally generated 1O2 excludes Type I photoreactions. The naphthalene derivative was, however, inactive against the non-enveloped viruses, adenovirus and poliovirus 1.394 In a similar approach, Käsermann and Kempf used a polymeric naphthalene endoperoxide compound (56) to thermally generate 1O2 to show its ability to inactivate the enveloped viruses SFV and VSV. As the endoperoxide compound is water-insoluble it can be removed from water-based solutions after the heterogeneous reaction.395


image file: c9pp00211a-f20.tif
Fig. 20 Systems for ‘storage’ and retarded release of 1O2 in anti-tumor PDT and for the PDI of viruses.

With respect to vaccine development, as well as related to the study of viral action mechanisms, it is often desirable to inactivate a virus but at the same time maintain certain functions of the virus for further studies. For example, octadecyl rhodamine B (52) has been found to deprive the Sindbis virus of its infectivity while maintaining its ability for membrane fusion.112 A photoactive analogue of the reverse transcriptase inhibitor Nevirapine 57, 9-azido-5,6-dihydro-11-ethyl-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepine-5-one (58), was used to inactivate the reverse transcriptase of HIV-1, but preserved the conformational and functional integrity of viral surface proteins (Fig. 21).109


image file: c9pp00211a-f21.tif
Fig. 21 Nevirapine and a photoactive analogue used for inactivating reverse transcriptase of HIV-1.

In 2010, a new broad-spectrum antiviral compound, termed ‘LJ001’, an aryl methyldiene rhodanine derivative (59, Fig. 22), was described.396 It was active against more than 15 different enveloped viruses, including Ebola virus, Marburg virus, IAV, HIV, Yellow fever virus, HCV, West Nile virus and VSV.396 Its effect was found to be based on the structural differences between more flexible cell membranes vs. more static viral membranes. LJ001 targets the viral lipid membrane and inhibits virus-cell fusion. The specific effect of the compound on the viral membrane has been elucidated in a publication from 2013 by Vigant et al.110


image file: c9pp00211a-f22.tif
Fig. 22 LJ001, an aryl methyldiene rhodanine derivative, active in vitro as a broad-spectrum antiviral and the optimized compound JL103, an oxazolidine-2,4-dithione.

The molecular mechanism of LJ001 was found to be dependent on the presence of oxygen and light. The antiviral activity of could be suppressed by 1O2 quenchers (sodium azide, 9,10-dimethylanthracene) or antioxidants (α-tocopherol), suggesting that LJ001 acts as a Type II PS. 1O2 results in allylic hydroxylation of double bonds in the unsaturated phospholipids of the virus membrane. This removal of double bonds and the concurrent introduction of hydroxyl groups in the lipid membrane core changes the biophysical properties of the viral membrane (disturbing membrane curvature and fluidity), hindering virus-cell fusion.110 LJ001 did not induce damage in cellular membranes, which the authors attributed to the cytoprotective system of eukaryotic cells against lipid peroxidation. Having elucidated this action principle and based on the drawbacks of LJ001 for in vivo application (i.e., limited stability), a new class of antiviral PSs was developed. These oxazolidine-2,4-dithiones, with red-shifted absorption spectra and higher 1O2 quantum yields showed an increased in vitro potency. One of the improved structures, ‘JL103’ (60) is shown in Fig. 22.110

The same research group also reported on the action mechanism of an antiviral compound belonging to the group of so-called rigid amphiphatic fusion inhibitors.111 This compound, ‘dUY11’ (61, Fig. 23), combines a large hydrophilic head group connected to a rigid and planar hydrophobic moiety which inserts into the viral membrane. The action of these compounds is thought to be based on their similarity in shape to lysophospholipids, which play a decisive role in virus-cell fusion. However, looking at the antiviral effect of dUY11, the authors found that it is dependent on light and oxygen, i.e., the inhibition of virus infectivity is absent in the dark and can be suppressed by the addition of a 1O2 quenchers (NaN3). Thus, dUY11 seems to be active via irradiation of its perylene moiety.111


image file: c9pp00211a-f23.tif
Fig. 23 dUY11, a rigid amphiphatic fusion inhibitor, whose antiviral activity is dependent on light and oxygen.111

The latter example sheds light on an intriguing (and complicated) aspect of the PDI of viruses: there are known PSs which may act via light-independent antiviral mechanisms (e.g., Temoporfin, 29). On the other hand, there may also be compounds with an undiscovered antiviral phototoxicity. This phototoxicity of known drugs is a general issue with regards to pharmacovigilance, e.g., the well-known statin Atorvastatin has been found to generate 1O2.397 The EMA [European Medicines Agency] has published specific guidelines to address this phototoxicity as a side-effect of known drugs.

BODIPYs or boron-dipyrromethenes (4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes) have found wide-spread application as fluorescent markers.398 With specific substitution patterns minimizing fluorescence and enhancing intersystem crossing to the triplet state, BODIPYs can also act as PSs, thus a variety of BODIPYs have been investigated for use in PDT.170,399 In this respect, the PDI of viruses has been addressed as well. For example, Carpenter et al. prepared the cationic BODIPY derivative 62 (see Fig. 24) and tested it against the inactivation of several bacterial strains and three viruses (DENV, VSV, and human AdV5) in the context of antimicrobial photodynamic materials.400 Infectivity reduction with the BODIPY was highest (6 log units) in DENV, followed by VSV (5 log units), and human AdV5 (2 log units).


image file: c9pp00211a-f24.tif
Fig. 24 A cationic BODIPY derivative with antibacterial and antiviral activity.400

These ex vivo decontamination applications for the PDI of viruses constitute a field of continuous interest for antiviral PSs, specifically for PSs that have long been known for their antimicrobial and antiviral activity (e.g., Rose Bengal).103,401 In this respect Rose Bengal has recently been proposed for the decontamination of wash water, using Escherichia coli BL21 and the bacteriophage T7 as model organisms.389 One advantage of these long-known PSs is the acquired knowledge on the toxicity and biological effects, facilitating application development.

4. Conclusion and outlook

In this review it was our intention to give an overview on the PDI of viruses roughly covering the last decade to identify lines of development and current fields of application. A multitude of different viruses have been shown to be susceptible to PDI in in vitro investigations. These investigations encompass long-known viruses but have also taken up challenges faced by newly emerged viruses and viral diseases, e.g., very recently with the case of the Zika virus. However, it is a long way from effectively killing viruses in suspension to a treatment in patients or elimination of viruses in complex media, such as blood products. A significant amount of clinical data on the PDI of viruses with different PSs and for different indications acquired years ago favored the bright prospects associated with phototreatment, whereas later this has focused more on specific applications and certain PSs already authorized for medical use.

With respect to PS development there is of course an ongoing interest in ‘classical’ PSs along the lines of phenothiazines, psoralens, tetrapyrroles (phthalocyanines, porphyrins), or riboflavins. Here, structural variations have been implemented and promising lead structures have been identified, e.g., amphiphilic cationic porphyrins which have been intensely investigated.10,75 Another interesting aspect is that the phototoxic effect of (well-known) PSs can in some cases easily be enhanced by combination with simple inorganic salts.165 Such combinations could facilitate the development of products for the PDI of viruses under a regulatory aspect. New compound classes which have been explored for their potential in PDI of viruses include carbon materials or, recently, the aryl methyldiene rhodanine derivatives or oxazolidine-2,4-dithiones.111 The elucidation of the mechanism of the rhodanine derivatives, which turned out to be based on photooxidation of virus envelope lipids, points to an important aspect in the PDI of viruses: compounds found to be active against viruses may have an undiscovered photodynamic action mechanism, and on the other hand there may also be ‘classical’ PSs (see Temoporfin)25a with a light-independent antiviral activity.

This underlines the requirement to assess the mechanism of antiviral activity for individual PS classes and individual PSs. Such specific investigations on the mechanism of antiviral activity (for example, discerning between Type I and Type II photosensitization) have appeared for a multitude of individual PSs and the current status on mechanistic investigations has been summarized in recent reviews.8a,10,204 Different antiviral mechanisms can be relevant for one compound class, e.g., fullerenes which act via Type I and Type II photosensitization but also show light-independent antiviral activity, or curcumin and hypericin which act as PSs but also show significant dark toxicity effects.122b,142,143

On the other hand, the psoralen derivative amotosalen, commercially applied in blood product decontamination, and 5-iodo-naphthylazide are examples for compounds which are photochemically active against viruses but do not rely on ROS for their antiviral effect. In general, the ‘unspecificity’ of the action of 1O2 and other ROS generated by PSs (or positively phrased, their ‘multi-target’ mode of action) is seen as an advantage with respect to possible resistance formation given the genetic flexibility of viruses and bacteria.14 The decade covered herein has seen first systematic investigations with respect to resistance formation in the PDI of viruses. For example, in a series of ten consecutive cycles of PDI against a bacteriophage with the cationic porphyrin 21 no development of resistance was observed.203 This supports the hope that the PDI of viruses is an option even for newly emerging strains of known viruses.

The nearer PS development gets to a medical/clinical application, the question of adequate pharmaceutical formulations becomes more important. For tumor therapy, the usually lipophilic PSs have been incorporated into suitable carrier vehicles, often nanoparticles.21a,c,22a,b With ALA, the treatment of HPV infections and its manifestations usually involves the same formulations as employed in tumor therapy. For other PSs used for PDI, (nano)particle preparations have been tested mostly in vitro, such as silica particles for phthalocyanines,310,311 nanoporous alumina or polyacrylonitrile nanofibers for porphyrins,208,219 liposomes for chlorins and phthalocyanines,285 or different nanostructured composites based on carbon materials.96,179,180,183–185,218 However, related to the PDI of viruses, the merging of PS and particles can also serve a different purpose: important fields for the application of PDI do not intend an administration directly to the patient, notably and most prominently the decontamination of blood products. Here, particle-based formulations may be advantageous as they can serve to inactivate viruses and may then be removed by adequate filter systems.96,285

Currently, there are three main medical and clinical areas for the PDI of viruses: the treatment of local HSV infections and the treatment of HPV infections (viral warts) with authorized PSs; predominantly ALA, but also HPD or methylene blue. A growing number of clinical investigations on PDI against HPV manifestations has appeared in recent years. Particularly, the clinical treatment of Condylomata accuminata has been investigated in detail. However, the field with the most practical relevance is probably the area of blood product decontamination. For this reduction/removal of viruses (and bacteria) from blood products, three PSs are in commercial use: Riboflavin, methylene blue, and the psoralen derivative amotosalen.18b,c Notably, two variants have been developed which do not rely on a PS: the alkylating agent amustaline (as a complement to amotosalen), which functions without light and can be used in whole blood, and, as a complement to the methylene blue/light treatment of blood products, the use of UV-C radiation.

Apart from this, the PDI of viruses has been investigated for several other medical applications such as eliminating the infectivity of viruses while maintaining their antigenicity/immunogenicity to provoke an immune response after vaccination or the use of PDI for the treatment of viral infections in animals, e.g., for fish-farming plants.18e,29,402

Recent years have seen a growing interest in non-medical applications of the PDI of viruses.196 For example, PDI has been proposed for food treatment,128b,402c,403 which is attractive as naturally occurring PSs such as curcumin or riboflavin are present in some food products anyway.

With respect to public health and viral safety a number of publications deal with the elimination of viruses from air/water using PDI,75,202,219 and the development of self-sterilizing materials and surfaces based on PS-loading.206,208,404 Specifically, inorganic materials have been evaluated in this context.162b,405,406 The use of inorganic materials, namely if employing inexpensive and environmentally friendly materials and sunlight as the natural light source offers considerable potential for this application of PDI. One example using a simple, inexpensive inorganic compound and sunlight is TiO2 photocatalysis for PDI of viruses.161,162 However, nanoparticle-sized TiO2 – occurring in an multitude of products – is investigated for potential health issues.407 In the context of viral safety, PDI has been proposed for the inactivation of viral samples in laboratory safety,18d and the PDI of viruses and bacteria has even been discussed as a measure for the destruction of biowarfare agents.4,163 Further investigations of such applications are to be foreseen.

The most used medical application of the PDI of viruses is currently the field of decontamination of blood products. However, with the application of ALA specifically against HPV manifestations, the PDI of viruses has also found entrance into clinical practice.

Looking at this multifaceted field of antiviral phototherapy, it becomes apparent that there is not ‘one’ specific PS or class of PS which is best suited for the PDI of viruses, but that it always depends on the specific application and virus target.

Significant knowledge has been acquired in mechanistic investigations related to the PDI of viruses, elucidating the relative importance of Type I and Type II photochemical processes. The principal mechanism of action of the PDI of viruses due to the unspecific action of ROS implies a low probability of resistance development and initial investigations on resistance development support this. Notably, several publications report a light-independent antiviral activity for some compound classes (e.g., fullerenes, tetrapyrroles). This is an interesting aspect for further investigations, as light-independent antiviral activity bears at least the principal option of a systemic application against viruses. In summary, given the rise of resistance against antivirals and the low probability of resistance formation, the PDI of viruses is a valuable support for the arsenal against viral diseases.

Abbreviations

AdVAdenovirus
ALA δ-Aminolevulinic acid
BoHVBovine herpes virus
BVDVBovine viral diarrhea virus
CoxCoxsackie virus
DENVDengue virus
EBVEpstein Barr virus
EIAVEquine infectious anemia virus
EMCVEncephalomyocarditis virus
FCVFeline calivirus
FHVFeline herpes virus
FVCFeline corona virus
HAHaemagglutinin
HALHexaaminolaevulinate
HAVHepatitis A virus
HBVHepatitis B virus
HCVHepatitis C virus
HIVHuman immunodeficiency virus
HMMEHaematoporphyrin monomethyl ether
HPDHaematoporphyrin derivative
HPVHuman papilloma virus
HSVHerpes simplex virus
IAVInfluenza A virus
IFNInterferon
ISCIntersystem crossing
JEVJapanese encephalitis virus
MALMethyl aminolevulinate
MIVMosquito iridovirus
MNVMurine norovirus
NDVNewcastle disease virus
NIRNear infrared
NPNanoparticle
NVNorovirus
SFVSemliki Forest virus
SODSuperoxide dismutase
PACTPhotodynamic antimicrobial chemotherapy
PCIPhotochemical internalization
PDIPhotodynamic inactivation
PDTPhotodynamic therapy
PEGPolyethylene glycol
PEIPolyethyleneimine
PpIXProtoporphyrin IX
PSPhotosensitizer
PVPPolyvinylpyrrolidone
ROSReactive oxygen species
RVRhinovirus
SFVSemliki forest virus
TNFTumor necrosis factor
UCNPUp-conversion nanoparticles
VEEVVenezuelan equine encephalitis virus
VSVVesicular stomatitis virus
ZnPc(Phthalocyaninato)zinc(II)

Conflicts of interest

A. Wiehe is employee of the biolitec research GmbH which belongs to the biolitec group. The biolitec Pharma GmbH, which is also part of the biolitec group, is the marketing authorization holder for the medicinal product Foscan® which contains the photosensitizer Temoporfin as the active substance.

Acknowledgements

The authors thank R. Wiehe for help with some graphics. This work was supported by a grant from Science Foundation Ireland (IvP 13/IA/1894) and has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 764837 (‘POLYTHEA’).

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