On the origins of SARS-CoV-2 main protease inhibitors

Abstract

In order to address the world-wide health challenge caused by the COVID-19 pandemic, the 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M^pro) coded by its nsp5 gene became one of the biochemical targets for the design of antiviral drugs. In less than 3 years of research, 4 inhibitors of SARS-CoV-2-M^pro have actually been authorized for COVID-19 treatment (nirmatrelvir, ensitrelvir, leritrelvir and simnotrelvir) and more such as EDP-235, FB-2001 and STI-1558/Olgotrelvir or five undisclosed compounds (CDI-988, ASC11, ALG-097558, QLS1128 and H-10517) are undergoing clinical trials. This review is an attempt to picture this quite unprecedented medicinal chemistry feat and provide insights on how these cysteine protease inhibitors were discovered. Since many series of covalent SARS-CoV-2-M^pro inhibitors owe some of their origins to previous work on other proteases, we first provided a description of various inhibitors of cysteine-bearing human caspase-1 or cathepsin K, as well as inhibitors of serine proteases such as human dipeptidyl peptidase-4 or the hepatitis C protein complex NS3/4A. This is then followed by a description of the results of the approaches adopted (repurposing, structure-based and high throughput screening) to discover coronavirus main protease inhibitors.

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Yves L. Janin

Dr. Yves L. Janin obtained his Ph.D. in Organic Chemistry in 1993 under the guidance of Dr. Emile Bisagni at the Institut Curie. Following two years of postdoc at the ICSN, Gif/Yvette and a year at the Danish School of Pharmacy in Copenhagen, he then worked for six years at the Institut Curie. After a sabbatical at the Vitry/Seine Aventis laboratories, he then joined the Institut Pasteur until 2022. He is now working at the Muséum National d'Histoire Naturelle in Paris. His interests lie in medicinal chemistry and NCEs as well as in the design of original bioluminescence-based reporting systems.

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Introduction

The protein encoded by the nsp5 gene of SARS-CoV-2 virus corresponds to the main protease of this coronavirus. This protein has also been named SARS-CoV-2 M^pro, 3C-like protease/3CLpro (CL for chymotrypsin-like) and C30 endopeptidase. Following N and O-terminal autocleavages, the mature enzyme is, at least,¹ able to hydrolyze 9 other conserved sites of the viral polyprotein produced by the host ribosome to generate the corresponding viral proteins. As well reviewed,^2–4 the protease features a characteristic cysteine/histidine catalytic dyad. It is the cysteine-145 thiol anion, depicted in Scheme 1, which acts as a nucleophile and the histidine-41 imidazole as a general base in the course of the proteolysis. The peptide 1 cleavage to release 3 and 4 takes place via the occurrence of transient S-acylcysteine (2) which is then hydrolyzed to regenerate the thiol function and release the protein 4. Peptide cleavage-wise, SARS-CoV-2 M^pro has the same hydrolysis selectivity as SARS-CoV-1 M^pro or other proteases from coronaviruses.^5,6 A recent report has actually described remarkable structural insights in this sequence recognition process.⁷ As depicted, the residue R₁ of any substrate has to be a glutamine, whereas, upward of the cleavage site, R₂ is usually a leucine or another hydrophobic residue, and if R₃ can vary, R₄ (which is not depicted) remains small and usually aliphatic. Downward, only the residue appears to be governing the cleavage selectivity as it can only be a serine, an alanine or an asparagine.⁷ Concerning host cell proteins, quite a few^8–11 have been reported as substrates of SARS-CoV-2 M^pro, thus providing further insights into the many ways^12,13 viruses play havoc in cellular biochemistry and innate immunity. A recent review on the proteins reported as substrates of this protease is also available.¹⁴

Scheme 1 Two stages of peptide 1 hydrolysis into 3 and 4 by SARS-CoV-2 M^pro.

Of note is that comparatively less inhibitors have been reported for the other SARS-CoV-2 protease which is a papain-like cysteine-bearing enzyme. Two papers^15,16 and a few reviews^17–20 would probably be good starting points for further information on this different viral protease. Moreover, and as far better reviewed recently,^21,22 the host cell lysosomal cysteine protease cathepsins B and L, the transmembrane protease serine 2 (TMPRSS2) and the subtilisin-like proprotein convertase furin, a calcium-dependent serine protease, are all capable of cleaving the viral spike protein coating the virus surface and this is an essential step for its cellular entry. Accordingly, in the absence of in vitro selectivity control, concerns have been raised on the true mechanism of observed antiviral effects for some series of unselective protease inhibitors reported,^23–25 not to mention the recurrent frequent hitters.^26–28 In fact, cathepsins B and L are actually the targets of a selective inhibitor which also displayed an antiviral effect in cellulo.²⁹ Moreover, as for past research against the MERS coronavirus (MERS-CoV),^30,31 the importance of these cellular proteases did suggest the use of camostat (5), an approved TMPRSS2 inhibitor, for treatment against COVID-19.³² However, even at high dose, the clinical trials with this anticancer agent pointed out a lack of any benefit.³³ Similar reasoning, originally based on MERS-CoV research,³⁴ has also led to trials (NCT04352400) with the nonspecific serine protease inhibitor nafamostat (6). The conclusions of these 2021 human trials against COVID-19 have yet to be published although the short in vivo half-life of this iminoimide will remain of real concern (Fig. 1).³⁵

Fig. 1 Structures of camostat (5) and nafamostat (6).

Two general approaches to discover inhibitors of serine or cysteine-bearing proteases have been used in the past. The main one is to design compounds which can arguably be described as covalent inhibitors. Such compounds will block the enzyme via the occurrence of a covalent bond with their catalytically essential OH or SH residues. Of note is that depending on the chemistry involved, the formation of a covalent bond can sometimes be reversed. The probably more difficult alternative is to discover inhibitors affecting the protease function because of a high and non-covalent affinity for either its catalytic site or another essential component of the enzyme. The latter approach can of course be useful for the former one since a well-placed incorporation of a reactive moiety into a high affinity compound will lead to a possibly more selective covalent inhibitor. Many reports have already listed all the, sometimes related,³⁶ inhibitors reported for their effect on chymotrypsin-like proteases of human rhinovirus,^37–40 enterovirus 71,⁴¹ SARS and MERS coronaviruses^42–46 and then SARS-CoV-2.^{2–4,6,17,18,47–70} In the present text, the many publications²⁶ solely based on in silico docking approaches^71,72 and/or on traditional/ancestral medicine beliefs which only described frequent hitters/pan-assay interference compounds (PAINS)^73–77 were ignored. This choice is a bid to discourage such all too obvious pollution of the scientific literature,^78,79 not to mention the issue of lack of reproducibility of some data from the academia.⁸⁰ Aside from these, quite a few virtual-based reports describe modest inhibition of SARS-CoV-2 M^pro by not too obvious frequent hitters which could lead to original series of inhibitors.^81–92 However, as for the published results of high throughput or X-ray based screenings,^84,93 we chose to wait for some reports focusing on the actual hit to lead progression before including them in this text.

Designing successful covalent inhibitors, a few examples

The principle for designing a successful/selective covalent inhibitor in general is to first start with a substance with a degree of specific affinity for the active site of the targeted enzyme. Then, the inclusion of an electrophilic and thus reactive component to the structure of such compounds can lead to a far stronger and possibly more efficient in vivo inhibition effect. A counter example, which unfortunately keeps on attracting undue attention and funding,⁹⁴ would be the frequent hitter⁷⁴ ebselen (7). This compound does feature a rather reactive nitrogen–selenium bond but very little else in its structure provides for any target selectivity. Indeed, a selective covalent inhibitor will rely on the principle that, when bound to its target, the reactive component of such a compound is oriented toward a nucleophilic and essential part of the enzyme in order to favor a reaction selectivity. This requires a fine-tuning process not only to improve the affinity of the non-reactive part of the inhibitor for its target but also to secure the best orientation of its reactive component. In other words, ebselen (7) does not comply with such criteria in contrast with, for instance, the recently authorized anticancer drug sotorasib/AMG 510 (8). Indeed, the latter features a Michael accepting acrylamide moiety along with other structural components providing an affinity for its biochemical target. Accordingly, this anticancer substance does preferentially lead to the occurrence of a covalent bond with the oncogenic KRAS (glycine 12 cysteine) mutant.^95,96 Of note is that more recent research, starting from BI-0474 (9), another covalent inhibitor of this KRAS mutant, actually led to the non-covalent pan-KRAS inhibitor BI-2865 (10).⁹⁷ Aside from providing a demonstration of the benefit of long-term research in medicinal chemistry, this illustrates the following facts: (i) in the course of designing inhibitors, it is indeed possible to add a reactive moiety and thus improve an inhibition effect and (ii) it is also sometimes possible to remove such a reactive moiety and, following some more structure-guided design of analogues, reach some very efficient non-covalent inhibitors (Fig. 2).

Fig. 2 Structures of compounds 7–10.

Concerning irreversible inhibitors of serine, cysteine or threonine proteases in general, a few reviews^98–101 provide an extensive description of the compounds reported. The following are only illustrations of some of the successes (and failures) of these classes of inhibitors.

Inhibitors of caspase-1/interleukin-1 converting enzyme

The cysteine protease caspase-1/interleukin-1 converting enzyme (ICE)¹⁰² cleaves peptides after an aspartic acid residue, preferably endowed with the sequence Tyr-Val-Ala-Asp. As reviewed,¹⁰³ research for specific inhibitors started with the aldehyde-bearing peptide Ac-Tyr-Val-Ala-Asp-H and using extensive structure-based insights, proceeded to replace/“deconstruct” most of these residues to reach more metabolically stable inhibitors. Belnacasan/VX-765 (11) is a hemiacetal prodrug, whose first patent application was filed by Vertex in 2000.¹⁰⁴ This compound will, upon a hydrolysis, leads to the aldehyde-bearing VRT-043198 (12), a selective covalent inhibitor of ICE. Of note is the nitrile group of analogue 13 which was introduced in 2010 as an alternative to the reactive aldehyde function of compound 11.¹⁰⁵ Aside from these, a few other series were also patented by Vertex. As depicted with the structures of the randomly selected N-substituted pyridinones 14 or 15, both “drifted” from the ICE-favored peptidic sequence mentioned above and their central heterocycle provided another type of structural lock to favor a suitable orientation of their reactive ketone.^106–108 The possible extent of such a peptide deconstruction approach is also well illustrated with the hemiacetal ICE inhibitor pralnacasan (16), which features a notable bicyclic piperazic component.¹⁰⁹ More recent work on the design of ICE inhibitors led another research group to uracil-containing derivatives such as the most advanced compound 17.^110,111 Clinic-wise, quite a few trials were conducted with belnacasan (11) for treatments of conditions involving a possible disfunction of ICE, but this class of inhibitors has yet to reach an approved use in human health. Of note is the current trend in addressing the dreadful cytokine storm seen in some SARS-CoV-2 infected patients by inhibiting the many biochemical pathways involved in inflammation. In this regard, a few 2022 patents claimed ICE inhibitors such as belnacasan (11) or the nitrile-bearing analogue 13 for their potential benefit against coronavirus infection.^112–114 Similarly, a recent patent¹¹⁵ claims the use of inhibitors of the beta secretase 1 to suppress this storm; however, both cases are quite outside the scope of this review (Fig. 3).

Fig. 3 Structures of interleukin-1 converting enzyme inhibitors 11–17.

Inhibitors of cathepsin K

Cathepsin K, which hydrolyses a rather wide range of substrates,¹¹⁶ was selected as a target to treat bone resorption. Extensive research at Merck led to the nitrile-containing inhibitor odanacatib (18)¹¹⁷ and an X-ray based structure further proved its mechanism of inhibition via covalent bonding with the catalytic cysteine residue.¹¹⁸ However, although this inhibitor reached a phase III clinical trial stage, its development was stopped in 2019 because of a stroke risk increase.¹¹⁹ Of note is the closely related analog CZ007 (19) which has been under consideration as a drug against the human parasite Trypanosoma cruzi since it also strongly inhibits cruzipain, a key cysteine protease of this protozoan.^120,121

Inhibitors of human dipeptidyl peptidase-4/CD26

As well reviewed,^122–127 the serine-containing dipeptidyl peptidase-4/CD26, which is a prolyl oligopeptidase, has many physiological roles. These include the proteolysis of glucagon-like peptide 1 or the glucose-dependent insulinotropic polypeptide, which are both key factors in glucose homeostasis. Since 1994, medicinal chemistry efforts have focused on cyanopyrrolidine-containing inhibitors and culminated in the discoveries of vildagliptin (20)¹²⁸ and saxagliptin (21).¹²⁹ With their nitrile function, both compounds are covalent inhibitors of this serine protease, although the serine adducts formed¹³⁰ are slowly reversible.^131,132 This class of covalent drugs have been prescribed for years to reduce hyperglycemia in patients with type 2 diabetes mellitus. Interestingly, many non-covalent inhibitors of this protease such as sitagliptin (22)¹³³ or alogliptin (23)¹³⁴ were also discovered. As demonstrated by X-ray based structures,^130,135 these non-covalent inhibitors also target the catalytic site of the protease and their wide structural diversity is a tribute to what can medicinal chemistry do (Fig. 4).

Fig. 4 Structures of compounds 18–23.

Inhibitors of hepatitis C serine protease NS3/4A

As described in an editorial on the 2020 Nobel Prize award to Harvey J. Alter, Michael Houghton and Charles M. Rice, the quest to first characterize and then discover treatments against hepatitis C infection has been a 30 year-long story.¹³⁶ Indeed, medicinal chemistry research on the inhibition of a number of viral proteins of hepatitis C virus has today delivered treatment efficacies nearing 95% cure!¹³⁷ Since the late 90s, many laboratories have focused on the design of covalent or non-covalent inhibitors of the hepatitis C serine protease NS3/4A.^138,139 The α-ketoamide-bearing covalent inhibitors boceprevir (24)^140–142 and telaprevir (25)¹⁴³ turned out to be the first clinically approved drugs. Interestingly, a proof of concept was also achieved in patients with the remarkable macrocycle ciluprevir/BILN 2061 (26) which is a non-covalent inhibitor of NS3/4A.^144,145 This discovery led to many series of macrocycle-bearing analogues which reached clinical approvals such as simeprevir (27)¹⁴⁶ or grazoprevir (28).¹⁴⁷ Finally, and as well accounted,¹⁴⁸ research on treatment of hepatitis C also focused on discovering inhibitors of its RNA-dependent RNA polymerase NS5B. This was concluded with the prodrug sofosbuvir (29) which is instrumental for reaching the 95% clinical efficacy mentioned above. However, this last achievement also triggered the voluntary withdrawal, or project termination, of quite a few hepatitis C serine protease NS3/4A inhibitors (Fig. 5).

Fig. 5 Structures of compounds 24–29.

Inhibitors of the SARS-CoV-2 main protease

Since the main proteases of SARS-CoV-1 and SARS-CoV-2 share a 96% amino acid sequence identity (but only 50% with the MERS-CoV main protease),² most if not all research on their inhibition turned out to be useful for the renewed projects focusing on improving such inhibitors. This was also the case for drugs which have been “repurposed” as inhibitors of MERS or SARS-CoV-1, and these include some potential inhibitors of their main protease.

Concerning drug repurposing

Aside from the excessive number of reports describing in vitro inhibition of SARS-CoV-1(or 2)-M^pro by well-known frequent hitters/PAINS, another approach focused on assessing libraries of drugs already or previously used or tried in humans. The SARS-CoV-2 pandemic thus saw the publication of many papers reporting in vitro inhibition of SARS-CoV-2-M^pro by such compounds. The main result of this approach is an unfortunate illustration of a lack of medicinal chemistry culture in general. Indeed, most often only micromolar level effects were observed in vitro for such drugs. Accordingly, it was more than unlikely that a patient would benefit from a treatment based on them, not to mention the issues of necessary dose increases which would be bound to lead to some side effects including some due to their main biological actions. In medicinal chemistry, compounds effective at the micromolar level against a given target can only be considered as hits (or early leads). Such compounds must undertake rounds of structure–activity relationship and selectivity studies to be further improved before preclinical and clinical trials can be envisaged. Attempts to cut this process short are oblivious to decades of experience in the domain and only slightly more rational than hoping for a miracle. Moreover, even in the rare event of finding a strong level of in vitro SARS-CoV-2-M^pro inhibition for a prescribed drug, it is very likely that it will lack any in vitro or in vivo selectivity. Indeed, quite a few highly reactive compounds are found in the present or past human pharmacopeia. In the following, we describe a few drugs which were reported for their effect on SARS-CoV-2-M^pro. Unfortunately, not all were the focus of some MedChem iterations to improve them before initiating wishful clinical trials which, predictably, led to disappointing results.^27,149–152

From a screening which identified 14 known drugs, the antiepileptic drug perampanel (30) was found to be an inhibitor of the main protease of SARS-CoV-2.¹⁵³ Some MedChem helped by X-ray based structures (PDB 7L10 to 7L14) from the same research group provided 3-pyridyl-bearing analogues, such as compounds 31 and 32 (with 32 being much less cytotoxic than 31).¹⁵⁴ And further work, helped by nine X-ray based structures in this case, gave improved inhibitors such as pyrimidinediones 33 and 34a,¹⁵⁵ as well as the even less cytotoxic N-methylated derivative 34b.¹⁵⁶ A more recent report has described analogues featuring a pyridone instead of the uracil moiety of compounds 33 and 34a–b.¹⁵⁷ As described in more detail below, the 3-pyridyl component of these improved analogues has actually been known since 2013 for its capability to interact with the histidine-163 of the SARS-CoV-1-M^pro catalytic site.¹⁵⁸ Also of note is that this class of inhibitors do have some structural similarities with alvelestat (35), a serine protease (elastase) inhibitor.¹⁵⁹ Independent from this work and as stated by its authors, a remarkably lucky de novo-initiated search for inhibitors delivered the somehow related (but not computer-guided) N-substituted pyridinone derivative 36. Further X-ray based crystallography studies are planned in order to improve its relatively modest inhibition level (Fig. 6).¹⁶⁰

Fig. 6 Structures of compounds 30–36.

A repurposed curiosity would be the veterinary anticancer drug masitinib (37), it is a tyrosine kinase inhibitor which has also been patented for its modest effect on the replication of SARS-CoV-2.¹⁶¹ Further research actually led to its co-crystallization with SARS-CoV-2-M^pro (PDB 7JU7).¹⁶² A note of caution would be that this rather sticky compound, as well as imatinib (38), has also managed to co-crystallize with human deoxycytidine kinase (PDB 5MQL).¹⁶³ In any case, undertaking clinical trials against COVID-19 (NCT05047783) with compound 37, even in association with the polyphenolic frequent hitter isoquercetin (NCT04622865), is very likely to be disappointing. Indeed, as mentioned for the repurposing of imatinib (38) against COVID-19, which has also been found active in vitro on MERS-CoV,¹⁶⁴ clinically achievable doses in humans will not be high enough to be effective against the virus replication.¹⁶⁵ One more example of such “sticky” compounds would be dasatinib (39), another tyrosine kinase inhibitor, which was reported to have some effect on SARS-CoV-2-M^pro.¹⁶⁶ However, the in cellulo antiviral effects observed for all these amine-bearing compounds are very likely due to drug-induced phospholipidosis.^167,168 This cellular-level effect (which impacts to some degree viral replications in cellulo) was unfortunately the cause of a considerable waste of money (as much as 6 billion dollars) when considering all the clinical trials against COVID-19 made with many amine-bearing compounds, especially chloroquine or hydroxychloroquine.¹⁵⁰ Concerning other cellular kinases, a recent report has described far stronger in cellulo inhibition of SARS-CoV-2 replication by PI3K/mTOR inhibitors such as sapanisertib (40).¹⁶⁹ Future will tell if this translates into an in vivo effect although a precedent would be the inhibitors of cellular dihydroorotate dehydrogenase¹⁷⁰ which have yet to translate into effective RNA-based antivirals (including corona) in patients.^171–173 In 2004, niclosamide (41) was found to be endowed with a degree of antiviral effect on SARS-CoV-1 although it was not found to inhibit its main protease¹⁷⁴ and later on, this anthelminthic drug was also reported for its effect on many viruses, which has been recently reviewed.¹⁷⁵ Finally, inhibition of SARS CoV-2 replication was also reported¹⁷⁶ and, despite some ongoing structure–activity relationship studies,¹⁷⁷ clinical trials were undertaken (NCT04399356 and 04603924)¹⁷⁸ with compound 41 and have so far failed.¹⁷⁹ Even if mechanism of action-wise, niclosamide (41) should not be mentioned here,¹⁸⁰ and some protease inhibitors such as 42 have a puzzling degree of structural similitude to this drug. Compound 42 actually resulted from attempts to prepare protease substrates which would release a fluorescent product. However, it turned out that that these were inhibiting SARS-CoV-2-M^pro and the ensuing structure–activity relationship studies led to this compound.¹⁸¹ More recent work on closely related analogues of compound 42 has reported very modest inhibition of SARS-CoV-2-M^pro.¹⁸² Another puzzling similarity is also seen with a patent¹⁸³ claiming the effect on SARS-CoV-2-M^pro of closantel (43), a rather toxic anthelmintic drug, which shares some degree of similitude to these two amides (Fig. 7).

Fig. 7 Structures of compounds 37–43.

Covalent or non-covalent inhibitors of SARS-CoV-2-M^pro from previous series

As for the series inhibiting other proteases, one of the approaches to design inhibitors started from the structure of small peptides featuring sequences recognized by the protease (i.e.: Ser-Ala-Val-Leu-Gln) and the addition of various types of warheads next to the cleavage site: downward the glutamine (Gln) residue in the case of SARS-CoV-2-M^pro. It would be beyond the scope of this review to depict all the series of peptide-derived inhibitors made, especially since 2019 an even larger array of warheads has been incorporated in such compounds.¹⁸⁴ Indeed, a non-exhaustive list used in the last few decades includes: aldehydes (or the corresponding bisulfite adduct),^41,185–202 ketones,^203–211 α-ketoamides,^{153,185,212–214} Michael acceptors,^{194,215–218} 4-iminooxazolidin-2-one,²¹⁹ reactive halogens,^220–224 β-lactam of some penicillins,^225,226 phenylsulfide,²²⁷ thiocyanate,²²⁸ epoxide,²⁴ nitriles^229–231 and, last but not least, alkynes.^232,233 Interestingly, aside from a 2005 patent²³⁴ targeting SARS-CoV-1-M^pro, the design of boron-containing inhibitors, which is a fairly classic approach for protease inhibition,^235,236 has not been reported in more recent time. Along with these warheads, intensive efforts were made to modify these peptides and/or replace them with non peptidic spacers. Moreover, compounds designed to block other viral cysteine proteases were of course assayed on the coronaviruses. As an illustration of the multitude of approaches, the Michael-acceptor bearing rupintrivir/AG7088 (44), initially designed in 1999 as a covalent inhibitor of human rhinovirus 3C cysteine protease,^237,238 was suggested²³⁹ in 2003 to be a starting point to target SARS-CoV-1-M^pro. A strong intensive to evaluate rupintrivir (44) was also the fact that it had previously been the subject of phase 1 and 2 clinical trials against rhinovirus.^240,241 However, rupintrivir (44) was “not able to significantly affect virus reduction or moderate disease severity and thus was terminated for clinical development”.²⁴² In any case, if compound 44 was reported inactive in 2005,²⁴³ the closely related analogue 45 turned out to modestly inhibit²⁴³ SARS-CoV-1-M^pro (or MERS-M^pro)²⁴⁴ and the longer peptides N1 (46) and N3 (47) featuring the more adapted Ala-Val-Leu sequence were even better.²⁴⁵ Although rupintrivir (44) was later found to only be a very modest inhibitor of SARS-CoV-2-M^pro, thanks to its reactive component, it still managed to co-crystallize with this protease (PDB 7L8I).²¹⁸ Also starting from the Ser-Ala-Val-Leu-Gln sequence, a research group reported in 2011 that the imidazole bearing aldehyde 48 was a modest inhibitor of SARS-CoV-1-M^pro. The ensuing structure-guided iterations of synthesis and evaluation led to the much stronger inhibitor 49 which was also co-crystallized with SARS-CoV-1-M^pro (PDB 3ATW).²⁴⁶ More recent work actually reported related imidazole-bearing peptides.²⁴⁷ Of note is that a glutamine residue is prone to cyclize at the least with ketone or aldehyde warheads.^248–250 Accordingly, effort to replace it also stemmed from the search for human rhinovirus 3C cysteine protease inhibitors and provided the bioisosteric lactams depicted in the structures of compounds 44 and 45. As well illustrated below, this bioisosteric replacement was repeatedly used in the structures of other virus protease inhibitors.^238,248,251 A recent review has actually described in much more detail this issue of glutamine replacement.²⁵² As for the results reported in 2000 focusing on the inhibition of the rhinovirus 3C protease,²⁰³ research on SARS-CoV-1-M^pro, dating from 2009, also explored the incorporation of large components downstream of the warhead. Similar to peptide inhibitors of the rhinovirus 3C protease,²⁰³ if the thiazole-2-ketone-bearing peptide 50 was only a modest inhibitor of SARS-CoV-1-M^pro,²⁵³ the benzothiazole analogue 51 in which benzene filled a pocket of this protease provided a thousand-fold improvement.²⁵⁴ Also of interest is the nitrile-containing peptide 52 which was reported in 2013 to be a weak inhibitor of SARS-CoV-1 M^pro, but it was established that this function could be used to covalently inhibit this protease (Fig. 8).²⁵⁵

Fig. 8 Structures of compounds 44–52.

The shorter bisulfite prodrug GC376 (53) was reported in 2012 as a norovirus 3CL protease inhibitor.²⁵⁶ As depicted, the bisulfite adduct 53 will release in situ the aldehyde function of the antiviral GC373 (54).²⁵¹ Interestingly, this compound has demonstrated a degree of in vivo effect against feline enteric coronavirus infection.^257,258 Even if it is only modestly effective in vitro²¹⁷ or in vivo against a mouse model of SARS-CoV-2 infection,²⁵⁹ this pan 3CL virus protease inhibitor has often been used as a positive control in SARS-CoV-2-M^pro assays. Many analogues of GC376 (53) were reported,^185,260,261 such as compounds resulting from a “fluorine walk” on the benzyl moiety and/or its replacement by a substituted cyclohexyl, a bulkier adamentyl and even more elaborated substituents.^{195,199,201,262,263} As an illustration of the “leeway” on this position, the difluorocyclohexyl-bearing analogue 57 was found to be effective against a mouse model of MERS coronavirus infection.¹⁸⁸ Moreover, a deuterated derivative of 50 was evaluated on a mouse model of SARS-CoV-2 infection but this analogue showed no real advantage.¹⁹⁸ This result may not be too surprising, since a deuteration strategy usually addresses fast metabolic issues but GC376 (53) was reported to be reasonably stable in human plasma (t_1/2 > 240 min) or in the presence of human liver microsomes (t_1/2 > 80 min) as well as in mice (t_1/2, plasma > 240 min, t_1/2, microsome > 80).²¹¹ Further studies on the protease inhibition selectivity of GC376 (53) as well as analogues EB54 (55) and NK01-63/coronastat (56) pointed out the fact that these compounds are also very strong inhibitors of the host cell cathepsin L.²¹¹ Another investigation reported even more analogues of GC376 (53) but also described solubility issues, along with suggestions to administer such bisulfite adducts at higher concentration.²⁶⁴ The cyclohexyl group of compound 49 was also adopted in the design of the related compound 58 targeting the norovirus 3CL protease.²⁶⁵ However, even combined with other types of warheads, this cyclohexyl feature turned out to be associated with cellular toxicity.^209,266 Compound TG-0205221 (59) illustrates the structure-based improvements made in 2006 when focusing on the inhibition of SARS-CoV-1-M^pro by this “Boc-derived” series.²⁶⁷ Much later, the O-tert-butyl-threonine component of the tripeptide TG-0205221 (59) was also found to be key to improving the interactions of related analogues with the P3 site of the SARS-CoV-2-M^pro binding pocket and it also provided some cellular potency.²⁶⁸ Interestingly, research at Glaxo, part of it dating from 2018 and focusing on the rhinovirus main protease,²⁶⁹ led to tripeptides such as 60 in which an α-ketoamide warhead was used instead of an aldehyde. However, a modest antiviral activity along with a degree of cellular cytotoxicity probably prevented further development of this series.²⁷⁰ The somehow larger “Boc” derivative 61 is amongst the compounds claimed in four patents by Cocrystal Pharma which has initiated a phase 1 study of the undisclosed coronavirus–norovirus protease inhibitor CDI-988 (NCT05977140) (Fig. 9).^271–274

Fig. 9 Structures of compounds 53–61.

Other series of short peptides were also designed when the world faced the first SARS epidemic. A 2005 patent claimed many isoleucine and lactam-containing inhibitors of SARS-CoV-1-M^pro, including the noteworthy indole-bearing derivative PF00835231 (62).²⁷⁵ In 2020, the corresponding phosphate prodrug PF-07304814/lufotrelvir (63) was then developed by Pfizer to fight COVID-19 infection,^205,276 and this intravenous prodrug²⁰⁷ underwent successful phase 1 clinical trials.^277,278 However, an additional trial (NCT05780541) was suspended by the FDA and lufotrelvir (63) was then withdrawn. More recent work borrowed the cyclohexane and the indole elements of 62 and led to aldehyde 64a or to the benzyl-bearing analogues 65 and 66.¹⁸⁹ Interestingly, FB-2001 (64a) was further evaluated²⁷⁹ and has undergone some clinical trials (NCT04766931). The same research group reported two years later that the non-fluorinated analogue 66 was better suited as a broad-spectrum antiviral since, aside from being active on SARS-CoV-2, it also displayed an effect on entero and rhinoviruses.⁴¹ Following extensive structure–activity relationship studies,²⁸⁰ Pardes Biosciences undertook clinical trials (NCT05011812 and NCT05543707) with the nitrile-bearing PBI-0451/pomotrelvir (67) which has also been co-crystallized with SARS-CoV-2-M^pro (8TBE). However, a company statement reported that this compound “did not meet the primary endpoint measured by proportion of participants below the limit of detection for infectious SARS-CoV-2 on day 3 of treatment” and further development was thus suspended.²⁸¹ The 3-methoxyindole-bearing analogue 68, also featuring the benzothiazole seen in compound 51, was initially designed against SARS-CoV-1-M^pro.²⁸² It was then reported to be efficient against SARS-CoV-2-M^pro and the virus replication.^206,210 An extensive study of various ester prodrugs such as compound 69 was reported and also demonstrated that no real difference in antiviral properties was observed between compounds featuring a 5 or a 6-membered lactam.²⁰⁹ In an approach which has been used in the past against rhinovirus 3C proteases²⁸³ and which incidentally addressed a racemization risk, the strong aza-bearing SARS-CoV-2-M^pro inhibitor YH-6 (70) featuring a chiral α,α-chlorofluoracetamide warhead was reported.²²³ Two patents^224,284 also claim related α,α-chlorofluoracetamide-containing aza-peptides including the fairly elaborated compound 71 which is effective against a whole panel of coronaviruses (Fig. 10).²²⁴

Fig. 10 Structures of compounds 62–71.

From the end of 2019, the hepatitis C serine protease NS3/4A inhibitors boceprevir (24) and telaprevir (25) depicted above, or the related narlaprevir, were repeatedly reported to be active in SARS-CoV-2-M^pro screening campaigns.^{153,186,187,285–287} This triggered X-ray based structural studies which pointed out that these reactive compounds did indeed bind to the catalytic site of SARS-CoV-2-M^pro.^212,287,288 Of course the bicyclic 3-azabicyclo[3.1.0]hexane component of boceprevir (24), which not only enables the removal of an NH moiety but also probably acts as a conformational lock, provided a lot inspiration for the design of many series of SARS-CoV-2-M^pro inhibitors. In fact, research conducted at Pfizer led, for instance, to the ketone-bearing inhibitor 72a or the nitrile-bearing PF-07321332/nirmatrelvir (73).^63,231 A crucial point explaining that nirmatrelvir (73) turned out to be orally active on a mouse model of SARS-CoV-2 infection is the removal of this extra NH moiety with this bicycle which greatly improved its diffusion.²⁸⁹ The ensuing successful clinical trials of nirmatrelvir (73) then provided the first approved SARS-CoV-2-M^pro inhibitor which must be prescribed in association with ritonavir to alter P4503A4-based metabolization and thus improve its pharmacology.^290,291 Interestingly, compound 72a was the focus of further optimization which led to the fluorinated derivative TKB245 (72b).^292,293 Moreover, an extensive search for an alternative to the trifluoroacetamide moiety of nirmatrelvir (73) was conducted at Ascletis Bioscience.²⁹⁴ The undisclosed protease inhibitor ASC11 probably resulting from this approach is currently undergoing Ascletis-sponsored phase 1 clinical trials, with the co-administration of ritonavir (NCT05718518). The 3-azabicyclo[3.1.0]hexane-bearing compounds MI-09 (74)¹⁹⁷ and UAWJ9-36-3 (76)²⁰⁰ or the cyclopenta[c]pyrrole-bearing inhibitors MI-30 (75)¹⁹⁷ and UAWJ-9-36-1 (77)²⁰⁰ also stemmed from this “structural lock” idea. Of note is that both 74 and 75 displayed in vivo antiviral effects as well.¹⁹⁷ The α-amido ketones MG-78 (78a) and MG-131 (78b) were designed according to similar lines and are very good inhibitors of SARS-CoV-2-M^pro as well.²⁹⁵ Additional α-ketoamide-bearing derivatives featuring such component also had an improved cell permeability.^296,297 Moreover, SARS-CoV-2-M^pro structures bound to such compounds have been released by two distinct research groups (PDB 7U92 and 7WQK). The notable cyclopenta[c]pyrrole-bearing SARS-CoV-2 M^pro inhibitor RAY1216/leritrelvir (79) was developed by Raynovent^298,299 and granted conditional market approval in China. Interestingly, this strong inhibitor also displayed an improved in vivo half-life in comparison with nirmatrelvir (73) and appeared to have been evaluated on COVID-19 patients with and without ritonavir or other P4503A4 inhibitors (NCT05620160).^300,301 A structure of SARS-CoV-2 M^pro bound to this compound has also been released (PDB 8IGN). The design and study of a related series of aldehyde-bearing compounds featuring various conformational locks actually reported that cyclopenta[c]pyrrole was amongst the most efficient pan-corona protease inhibitor in cellulo.³⁰² The dithia-7-azaspiro[4.4]nonane derivative 80 is a strong SARS-CoV-2 M^pro inhibitor which was developed by Simcere Pharmaceutical. In association with ritonavir,³⁰³ it has also been granted conditional market approval in China under the name Xiannuoxin/simnotrelvir^304–306 and the results of phase 1 clinical trials (NCT05339646) were reported recently.³⁰⁷ The undisclosed SARS-CoV-2 M^pro inhibitor ALG-097558 is developed by Aligos therapeutics, possibly without a co-administration of ritonavir and phase 1 clinical trials have been initiated (NCT05840952).²⁵ Three distinct patents,^229,308,309 from this company and the Catholic University of Leuven, describe a large number of compounds featuring a variety of conformational locks. We (randomly) choose to depict the 5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane] derivative 81, since this strong SARS-CoV-2 M^pro inhibitor also illustrates what MedChem is about: innovation in chemistry leading to original and thus patentable compounds. The simpler azabicyclo[2.2.1]heptane ring system has also been introduced in the structure of such inhibitors.³¹⁰ Further insights were provided in the course of an extensive study of boceprevir analogues which reported some key elements to achieve an antiviral effect in cellulo.³¹¹ Moreover, the same research group recently reported the azaspiro[4.4]nonane derivative MPI-60 (82), which displays promising antiviral properties³¹² and a structure of SARS-CoV-2 M^pro bound to this compound was obtained (8STZ). Finally, CMX990 (83), an azaspiro[2,4]heptane-bearing derivative, is also a tribute to the creativity required in MedChem and this compound has reached the stage of phase 1 clinical trials.^313,314 This ring system and quite a few others were actually also described in a paper from another research group.³¹⁵ Moreover, many strongly effective azapeptides, including some α,α-chlorofluoracetamide-containing derivatives²⁸⁴ related to 70 and 71 and featuring such conformational locks, have been claimed.³¹⁶ Finally, the bisulfite prodrug of the aldehyde derivative AC1115 (64b), a covalent inhibitor of SARS-CoV-2-M^pro and cathepsin L³¹⁷ has undergone successful clinical trials under the names STI-1558/OVYDSO/Olgotrelvir without the recourse to ritonavir. These trials were sponsored by Sorrento therapeutics/Zhejiang ACEA Pharmaceutical (NCT05716425 and NCT06044233). Interestingly, the corresponding patent is claiming a wide range of SARS-CoV-2-Mpro inhibitors featuring structural elements seen in compounds 62–83 (Fig. 11).³¹⁸

Fig. 11 Structures of compounds 72–83.

Also of interest, the SARS-CoV-2 M^pro inhibitor EDP-235 (85) from Enanta Pharmaceuticals³¹⁹ recently met the primary end point of a phase 2 clinical trial without the coadministration of ritonavir (NCT05616728). In this case, 13 patents from this company claim a very large variety of peptides sometimes featuring conformational locks related to the one depicted above. Amongst them, compound 84 (ref. 320) not only features a cyclopenta[c]pyrrole in its structure but its warhead is a cyanopyrrolidine, reminiscent of vildagliptin (20) or saxagliptin (21). This cyanopyrrolidine is also rigidly connected to an indolinone which acts as the bioisoster replacement of the glutamine. Many more compounds featuring such unprecedented spiropyrrolidine along with a variety of warheads were claimed. EDP-235 (85),³²¹ which is also the subject of two process patents for its large-scale production,^322,323 or compound 86 (ref. 324) are noteworthy for their N-methyls. The NH homologs of these compounds were also made but their antiviral effects were apparently not deemed of sufficient interest to be mentioned in the corresponding patents.^321,324 Interestingly, the structurally very constrained macrocycle 87 (ref. 325) and the simplified compounds 88 (ref. 326) and 89 (ref. 327) were also patented as effective inhibitors of SARS-CoV-2 M^pro (Fig. 12).

Fig. 12 Structures of compounds 84–89.

The research on inhibitors of the rhinovirus 3C protease conducted at Agouron/Pfizer at the turn of the century, which provided rupintrivir (44), also led to 2-pyridone-bearing analogues of this peptide.^328–330 Amongst them, the orally available inhibitor AG7404 (90) underwent two phase 1 clinical trials,³³¹ the latter, under the drug name V7404, was sponsored by ViroDefense and focused on enterovirus infection.³³² As for rupintrivir (44), this alkyne-bearing compound was reported in 2022 to modestly inhibit SARS-CoV-1 and SARS-CoV-2 main proteases and it was co-crystallized with both enzymes (PDB 7ZQW and 7ZQV).³³³ By following this approach, which consists of rigidifying the P2–P3 amide bond of the protease substrate, the pyridinone derivative (91) was designed and reported to inhibit SARS-CoV-2 M^pro. Moreover, this compound demonstrated an effect on cell-based virus replication assays.²¹² Interestingly, it was shown that the (S) enantiomer depicted here was the most active although the corresponding (R) enantiomer also had a degree of effect. In fact, even if the (R) isomer was 50 times less efficient as a protease inhibitor, both isomers co-crystallized within the SARS-CoV-2 M^pro catalytic site (PDB 8A4T and 8A4Q) with rather drastically different binding modes.²¹⁴ This probably illustrates the non-selectivity bias induced by a reactive component in a given molecule. Indeed, if such a compound can reach the nucleophilic part of the biochemical target, it is reasonable to assume that it will react with it, in spite of having a low overall affinity for the binding site. This known bias actually led in 2011 to the following comment: “the stringent substrate specificity of the SARS-CoV M^pro with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead. This constitutes a deviation from the dogma that peptidic protease inhibitors should comprise an amino-acid sequence corresponding to the cleavage specificity of the target enzyme”.³³⁴ This comment is also likely valid for a number of aldehyde-bearing compounds which have been reported to be inhibitors of SARS-CoV-2 M^pro.^91,196,335 In any case, a patent describes further structure–activity relationship studies around such pyridone derivatives which led to the modest SARS-CoV-2 M^pro inhibitor 92.³³⁶ In a 2013 patent, an array of inhibitors, such as the constrained azapeptide 93 featuring a rigidifying 2,6-dioxopiperidine component,³³⁷ or macrocyclic-bearing peptides such as 94,³³⁸ were claimed for their effects on 3CL proteases of picornaviruses, caliciviruses and coronaviruses. The related 3-amino-6-oxopiperidine spacer was also employed more recently and for instance, compound 95 turned out to be an effective SARS-CoV-2 M^pro inhibitor (Fig. 13).³³⁹

Fig. 13 Structures of compounds 90–95.

Amongst SARS-CoV-1 M^pro covalent inhibitors of less interest, many 3-pyridyl esters with the general formula 96 were reported between 2004 and 2008.^340–343 It was then demonstrated³⁴¹ by mass spectroscopy that these aryl esters (unsurprisingly) react with the cysteine of the protease. Later on, some compounds were shown to also strongly inhibit SARS-CoV-2 M^pro but again these had a very modest antiviral effect.^194,206,344 A more recent report provided an extensive demonstration of their chemical reactivity and further established that these compounds were probably the focus of too much attention in view of their lack of potential in medicinal chemistry.³⁴⁵ Another recent report has actually described covalent inhibitors in which the activated carboxyl was replaced by a sulfone conjugated to a reactive oxadiazole ring system,³⁴⁶ and carmofur analogues also featuring an activated carboxamide side chain were reported.³⁴⁷ Moreover, somehow related thioesters have been reported to similarly react with the catalytic cysteine and displayed rather strong in cellulo antiviral effects.³⁴⁸ It remains to be seen if such compounds will retain some stability in vivo. To address this issue, an attempt was made in 2008 to replace the ester function of compounds 96 by a ketone, as seen in the structure of analogue 97, but the results were disappointing.³⁴⁹ More interestingly, in 2013, a high throughput screening for inhibitors of SARS-CoV-1 M^pro, using the 293 000 compounds of the NIH molecular library, discovered more elaborated 3-pyridyl-bearing compounds such as ML188 (98) or benzotriazole derivatives such as ML300 (99).^158,350 One of the reports also included an X-ray based structure of ML188 (98) bound to SARS-CoV-1 M^pro (PDB 3V3M),¹⁵⁸ and much later on, both inhibitors were co-crystallized with SARS-CoV-2 M^pro (PDB 7L0D³⁵¹ PDB 7LME³⁵²). Of note is that these inhibitors bind to the catalytic site via key interactions between the imidazole ring of SARS-CoV-2 M^pro histidine-163 and their pyridine or benzotriazole nitrogen. Moreover, for these inhibitors the protease glutamine-166 NH usually interacts with their recurrent carboxamide functions situated four “bonds away” from these nitrogens. As illustrated below, this pattern is recurrent in most of the 3-pyridyl-bearing inhibitors of SARS-CoV main proteases (Fig. 14).

Fig. 14 Structures of compounds 96–99.

By the end of 2019, these 2013 results became the starting point of research projects in many laboratories. In full collaboration with a large X-ray based facility, many structures of 3-pyridyl-bearing compounds bound to SARS-CoV-2 M^pro were thus made available.⁹³ Such structures were instrumental for the open science COVID Moonshot initiative which undertook a publicly available drug discovery project based on the iterative process required to improve 3-pyridyl-bearing compounds such as ML188 (98).^353–357 As described,^358,359 in one attempt, the COVID Moonshot initiative went from 3-pyridyl derivative TRY-UNI-714a760b-6 (100) to isoquinoline derivatives such as ADA-UCB-6c2cb422-1 (101), MAT-POS-b3e365b9-1 (102) or PET-UNK-29afea89-2 (103). In fact, these compounds became more and more elaborated not only to strengthen their affinity for the SARS-CoV-2 M^pro catalytic site but also to start addressing the myriad of problems associated with an eventual in vivo use. The next two inhibitors MAT-POS-4223bc15-23 (104) and VLA-UCB-29506327-1 (105) illustrate some more possibilities for further iterations which required extensive profiling before choices were made. Meanwhile, another group also reported some related inhibitors using a docking-based virtual screening along with an X-ray based structure of the derivative X77 (112) bound to SARS-CoV-2 M^pro (PDB 6W63). Interestingly, from the 3-pyridyl derivative 106 discovered with this strategy, the ensuing optimization led to the 300-fold more active inhibitor 107.³⁶⁰ Moreover, out of a virtual screening using an X-ray based structure (PDB 6Y2G) of SARS-CoV-2 M^pro covalently bound to the α-ketoamide inhibitor 91 depicted above, another research group also reported many (modest) hydantoin-bearing inhibitors related to compounds 105–107 (Fig. 15).⁹¹

Fig. 15 Structures of compounds 100–107.

Starting from the less deconstructed ML188 (98), the analogues 108 and 109,³⁶¹ or the related MAT-POS-f2460aef-1 (110),³⁵⁶ explored some other possibilities and the more elaborated pyrazine-bearing analogue 111 was also reported.³⁶² The design and synthesis of the analogue X77 (112) was never actually reported but this compound was co-crystallized with SARS-CoV-2 M^pro in 2020 and the corresponding X-ray based structure (PDB 6W63) has been repeatedly used for virtual-based approaches. Finally, a search starting with DNA-encoded chemical libraries led to the very strong SARS-CoV-2 M^pro inhibitor 113. As demonstrated by X-ray studies (PDB 7UR9), the isoquinoline moiety of this compound does bind to the protease catalytic site in the same way the series depicted above do (via a hydrogen bond with His-163). However, in one instance in these series, replacing this isoquinoline by a pyridine led to a rather unexpected complete loss of activity (Fig. 16).³⁶³

Fig. 16 Structures of compounds 108–113.

Finally, many research groups resorted to the incorporation of a reactive component in these series.¹⁸⁴ As depicted, an acrylamide was used for compound 114,³⁶⁴ and an α,α-dichloroketone for compound 115.²²¹ Of note, the recourse the α,α-chlorofluoracetamide moiety seen in the structures of compounds 70 and 71 was claimed for these series as well,³⁶⁵ and an X-ray based structure of SARS-CoV-2 M^pro covalently bound to the notable Jun10-90-3-C1 (116) has been released by another research group (PDB 8D4P). Out of two large patents from Pardes Biosciences, the randomly chosen α-aminonitrile 117 or even more reactive 1-aminonitriles are additional illustration of this approach.^366,367 A report describes a quite systematic introduction of an array of electrophilic moieties leading for instance to the chloroamide 118.³⁶⁸ Even more reactive analogues are described in another publication¹⁸⁴ and in a patent.³⁶⁵ Also of interest is the rather large α-ketoamide derivative Y180 (119) which turned out to be an orally available inhibitor of SARS-CoV-2 M^pro endowed with a degree of antiviral effect in vivo.³⁶⁹ In another original approach, two patents from Novartis claim compounds such as the very strong inhibitors 120 (ref. 370) or 121 both combining quite elegantly a reactive nitrile and structural features seen in this class. Concerning the series encompassing compound 121, many analogues claimed in the patent³⁷¹ do not feature a reactive moiety. Finally, the incorporation of a probably less reactive and hindered nitrile as seen in the structure of MAT-POS-e194df51 (122),^356,358 or the more constrained MIK-ENA-5d9157e9 (123), provided some of the most advanced inhibitors of the remarkable COVID Moonshot initiative.³⁵⁹ In fact, compound 122 does not bind covalently to SARS-CoV-2 M^pro as demonstrated by the X-ray based structure code P1788 accessible on the Fragalysis website (Fig. 17).³⁷²

Fig. 17 Structures of compounds 114–123.

Interestingly, another class of isoquinoline-bearing inhibitors of SARS-CoV-2 M^pro (in which this heterocycle also interacts with His-163, see PDB 7EN8) was found with the combined use of a DNA encoded chemical library and docking-based ranking. This resulted in WU-04 (124) which features a so far required nitro group (for its notable interaction with the backbone CO of the protease Arg188) and is effective in vivo on a mouse model of infection.³⁷³ Similar series of nitro-bearing compounds were the focus of extensive structure–activity relationship studies by another research group and were, so far, only illustrated by a recent patent from Qilu Pharmaceuticals.³⁷⁴ Moreover, clinical trials of the undisclosed QLS1128 have been initiated by this company (NCT05458076). The benzotriazole-bearing inhibitor 99 reported³⁵⁰ in 2013 was also the focus of some more research. The MedChem efforts of the COVID Moonshot initiative led to improved analogues such as ALP-POS-6d04362c-2 (125).³⁵⁶ The imidazole-bearing analogue CCF981 (126a) was the fruit of extended SAR studies, although this work also pointed out that strong cytochrome P450 inhibition appeared to be a recurrent issue for these benzotriazole derivatives.³⁵² Another report describes the triazole replacement by a 3-pyridyl moiety, as seen in the structure of compound 127, which led to a less efficient inhibitor in comparison with 126b. But then, the same research group used an isoquinoline and this provided the powerful SARS-CoV-2 M^pro inhibitor 128 (ref. 375), and many more examples, patented by the Cleveland Clinic Foundation, claim a range of inhibitors featuring alternatives to this benzotriazole.^376,377 A recent report has also described additional analogues such as compound 129 which combines structural elements of compound 125 as well as 5-hydroxyisoquinoline. The X-ray structure of this inhibitor bound to SARS-CoV-2 M^pro was obtained (PDB 8SXR) and showed that the isoquinoline nitrogen also interacts with the histidine residue 163 of the protease.³⁷⁸ Many strong inhibitors, in which the usual lactams were replaced by a whole array of other bioisosters, were patented by the Global Health Drug Discovery Institute.³⁷⁹ This patent is illustrated by compound 130, which combines peptidic elements and a 3-pyridyl moiety. Moreover, patents from Exscienta or Pardes claim related compounds featuring even more varied heterocycles acting as lactam/3-pyridyl bioisosters.^380,381 It is also very likely that an undisclosed derivative of 130 is undergoing clinical trials, sponsored by Jiangsu Hansoh Pharmaceutical, under the name H-10517 (NCT05779579). Finally, a recent patent from Merck³⁸² claims a whole array of inhibitors such as compound 131 which feature a remarkable difluorinated side chain instead of the recurrent lactam. A 2007 paper is actually describing analogues of Boceprivir inhibiting the HCV NS3/4A protease and featuring related difluoromethylene components on the same position.¹⁴¹ In a way, these last two compounds feature most of the hard-won lessons of many structure–activity relationship studies and la boucle est bouclée (the circle is complete). From them, it is actually tempting to suggest to alter the non-covalent 3-pyridyl bearing series of inhibitors by replacing their 3-pyridyl with all the other groups described although it may be a real chemical challenge in some instances (Fig. 18).

Fig. 18 Structures of compounds 124–131.

Original SARS-CoV-2-M^pro inhibitors

Aside from all the inhibitors described above, which are arguably continuations of the research made on the inhibition of various viral proteases, including SARS-CoV-1 M^pro, one original approach involved the generation of a large number of random peptidic sequences which were then assayed. If a similar but more virtual-based approach failed in an early instance,³⁸³ this also led to all D-peptides^384,385 or to macrocyclic 11–14-mer peptides featuring modified amino acids³⁸⁶ endowed with affinities for the SARS-CoV-2 M^pro catalytic site. In the latter case, the corresponding X-ray based structure (PDB 7Z4S) may be of future use to deconstruct such rather large peptides into more drug-like compounds. Concerning smaller compounds, a docking-based approach, using half a million bioactive compounds and the structure of SARS-CoV-2 M^pro bound to the peptide derivative 47 (PDB 6LU7), has to be followed by more virtual-based selections, taking into account known inhibitors. This led to the very modest inhibitor 132 featuring a pyrimidinetrione component. A sulfamide derivative was also discovered by the same group but has yet to be developed.³⁸⁷ The related pyrimidinedione 133 was the result of another virtual screening of 6.5 million compounds commercially available using an array of X-ray based structures of SARS-CoV-2 M^pro bound to various inhibitors (compounds 47, X77 (112), telaprevir (25) and masitinib (37); see PDB 7BQY, 6LU7, 6W63, 7C7P, and 7JU7).³⁸⁸ Following this achievement, an X-ray based structure of pyrimidinedione 133 bound to SARS-CoV-2 M^pro was obtained and led to a medicinal chemistry program which has so far provided only modest results.³⁸⁹ Interestingly, another hit to lead project also started with compound 133 and led to the improved GC-14 (134) in which the pyrimidinedione was replaced by the recurrent 3-pyridyl component which interacts with the SARS-CoV-2 M^pro His-163 residue (PDB 8ACL). A replacement with an isoquinoline instead led to the same level of inhibition.³⁹⁰ Unexpectedly, adding instead an α-chloroketone warhead, as depicted for compound 135, had a deleterious impact on the antiviral effect as compared with GC-14 (134).³⁹¹ However, only a modest antiviral effect was observed in cellulo for compound 134, possibly because of a low cell membrane permeability. From the non-covalent pyridyl-bearing inhibitors listed above, a computer-based “synthesis-directed de novo design model” provided the non-obvious quinolone 136 which has a degree of effect on SARS-CoV-2 M^pro as well as on the seasonal OC43 coronavirus.³⁹² Interestingly, the related inhibitor JZD-07 (137) which gathers features found in 133 and 136 was reported later. In this case, it is the quinolone oxygen which is the bioisosteric replacement for the 3-pyridyl nitrogen (PDB 8GTV), and this inhibitor is endowed with an in vivo efficacy against a mouse model of SARS-CoV-2 infection.³⁹³ A related analogue (JZD-26) has been co-crystallized with SARS-CoV-2 M^pro (PDB 8GTW) although a corresponding publication is still expected. The COVID Moonshot initiative also explored related quinolones such as the less rigid but rather modest inhibitor MAT-POS-3b536971-1 (138).³⁵⁶ Another series of 3-pyridyl-bearing inhibitors of SARS-CoV-2 M^pro such as the rather rigid compound 139 were also patented (Fig. 19).³⁹⁴

Fig. 19 Structures of compounds 132–139.

Experimental screenings along with medicinal chemistry approaches were also used to search for SARS-CoV-2 M^pro binding inhibitors. The α-ketoamide 140, with its 2-pyridyl actually interacting with His-163 (PDB 7AEH),³⁹⁵ and compound 141 (ref. 396) were found in the course of a FRET-based screening of a chemical library of 30 000 compounds. The ensuing structure-based (PDB 8HHT) hit to lead progression led to a hundred-fold more active SARS-CoV-2 M^pro inhibitors such as compound SY110 (142).³⁹⁶ A remarkable feature of this original class of peptidic and covalent inhibitors is the absence of the lactam bioisoster of the glutamine residue seen in the many series depicted above. Earlier examples have actually been reported for a modest effect on SARS-CoV-1 (ref. 397) or SARS-CoV-2 multiplication, although in the latter case, these compounds were inhibiting other proteases and had anticancer properties as well.³⁹⁸ Since SY110 (142) displays a robust pan-coronavirus antiviral effect, an original binding mode to the catalytic site (PDB 8HHU), and good preclinical characteristics and is effective in a model animal of COVID-19 infection, further work on this class of inhibitors appears to be warranted. Another recent attempt focused on the variety of sequences found in the substrates of SARS-CoV-2 M^pro including downstream of the cleavage site and the determination of X-ray based structures. This led to the recognition that the peptide Ala-Ile-PheOMe, derived from VKLQAIFR, a larger peptide which has been co-crystallized with SARS-CoV-2 M^pro (PDB 8GWS), retained a degree of affinity for the enzyme. Then, the addition of a warhead onto this peptide and some structure-based improvements led to compounds such as the α-bromoacetamide 143 which is a modest inhibitor of SARS-CoV-2 M^pro and viral replication.³⁹⁹ It is possible that this original work along with the structure of 143 bound to the protease catalytic site reported (PDB 8JPQ) will pave the way for many research projects focusing on the discovery of non peptidic inhibitors targeting this previously unexplored pocket. The strong SARS-CoV-2 M^pro binding inhibitor and vinylsulfoxide-bearing PM-2-071 (144) was reported following a screen of 582 acrylamide or chloroacetamide-bearing compounds and some hit optimization.⁴⁰⁰ However, the toxicity issue of vinylsulfoxide-bearing compounds should be kept in mind for further development of this type of Michael acceptor.¹⁸⁴ The α-chloroamide-bearing benzodiazepine 145 was also found to be a modest inhibitor of SARS-CoV-2 M^pro following the screening of 5000 compounds. The ensuing hit progression has so far provided compound 146 with only a modest 10-fold improvement of activity, despite the obtention of an X-ray based structure (PDB 8JOP).⁴⁰¹ Finally and to conclude this part, the truly original and authorized antiviral drug ensitrelvir/S-217622 (149) was discovered in the course of a virtual-based selection using, again, the structure of SARS-CoV-2 M^pro binding X77 (112) (PDB 6W63).⁴⁰² This selection from hundreds of thousand compounds of an in-house chemical library led to a smaller screening and the identification of compound 147 which has been made years before in the course of a research program focusing on the design of analgesics.⁴⁰³ An X-ray structure (PDB 7VTH) then revealed its binding mode and the ensuing hit to lead program proceeded, via compound 148, to reach ensitrelvir (149). Of note is that as seen in the X-ray based structure, it is the triazole ring which interacts with the His-163 residue for this class of inhibitors (PDB 8DZ0).⁴⁰⁴ In fact, closely related analogues featuring, amongst other heterocycles, the recurrent 3-pyridyl group instead were claimed later.⁴⁰⁵ The clinical trials^406–408 of ensitrelvir (149), sponsored by Shionogi, turned out to be successful and this is so far the sole non-covalent SARS-CoV-2 M^pro inhibitor approved as an emergency treatment of COVID-19 in Japan. It is currently undergoing phase 3 clinical trials across the world (NCT05605093 and NCT05305547). Two more recent patents have focused on analogues of ensitrelvir (149), the first claims various deuterated analogs which may have improved pharmacological properties,⁴⁰⁹ and the second has undertaken a rescaffolding of the core 1,3,5-triazine ring and claims analogs featuring a 1,2,4-triazine ring system instead (Fig. 20).⁴¹⁰

Fig. 20 Structures of compounds 140–149.

Conclusions

The list of chemicals described above is only representing a portion of all the compounds which have been evaluated around the world on many types of assays targeting SARS-CoV-2 M^pro. In spite of belief-based treatments (using natural or human-made compounds) which unfortunately mobilized a lot of money and claimed an unacceptable number of lives¹⁵⁰ and in spite of far too many unexploitable⁷¹ computer-involving reports (and patents) which also attracted much funding and raises acute questions on some authors, reviewers (if any), editors and publishers' integrity,⁷⁹ some approaches did deliver useful drugs. If drug repurposing was, as for the previous coronavirus epidemics, an unmitigated and unfortunately predictable failure,^{151,152,411,412} past research results on various proteases as well as renewed screenings turned out to be successful starting points. Moreover, as probably not enough emphasized here, the staggering number of X-ray based structures solved greatly helped the resulting hit to lead progressions. A 2014 review on this subject does remain quite relevant.⁴² As described above, except for ensitrelvir (149), all the most advanced or authorized inhibitors of SARS-CoV-2 M^pro owe their effect to the occurrence of a covalent bond with its catalytic cysteine. Interestingly, in a description of the invention of nirmatrelvir (73),^289,413 the choice of the chemically reactive component to be used (nitrile or the ketone function of analogue 72 in this case) remained a difficult one. This was the subject of some investigations,^193,414 especially in light of the metabolic and cytotoxicity concerns with aldehyde-bearing covalent inhibitors.²⁶⁸ In one instance,⁴¹⁴ a systematic survey was made using the nirmatrelvir (73) structure as a template. From this work which provides precise biochemical and cell-based insights into warhead selection, another quite puzzling result emerged. In fact, if nirmatrelvir (73) or the corresponding ketone-bearing analogue 72b is a really effective inhibitor of SARS-CoV-2 M^pro, the peptides lacking these reactive moieties, such as the decarboxylated derivative 150 or the alcohol 151, are devoid of inhibition effect. This experimental fact is in contrast with what is observed for the KRAS inhibitors 8 and 9 depicted in Fig. 2, since the analogues lacking their acrylamide moiety are still capable of modest inhibition of this kinase. This suggests that, upon the chemical reaction between the warhead of covalent inhibitors and the cysteine of the SARS-CoV-2 M^pro catalytic site, a conformational shift occurs and the newly formed pocket can then bind to some more elements of these inhibitors. Even the ester function of compound 152 which, once this compound settles in the catalytic site, could react with the thiol function, does not. This suggests that 152 never binds to SARS-CoV-2 M^pro and this implies that before a reaction takes place with the cysteine thiol of SARS-CoV-2 M^pro, the catalytic site has a conformation devoid of affinity for the other components of these inhibitors. This could mean that ligands specific to this unknown site conformation have yet to be identified as such. At least one early report on the clustering of various inhibitors of SARS-CoV-2 M^pro according to the shape of the pocket binding to them does point out a degree of flexibility.⁴¹⁵ But to account for the complete lack of affinity of compounds 150–152 for the SARS-CoV-2 M^pro catalytic site, one could suspect far larger conformational changes. In fact, one way to detect and characterize such non-obvious conformations remains extensive high throughput screenings for fully original and non-covalent inhibitors, followed by X-ray based structural studies of their interactions with the protease. From the chemistry point of view, many compounds described here are tributes to the creativity of organic chemists. Of note would be the oxidative rearrangement of the tetrahydrocarboline 153 into the spiropyrrolidines 154 and 155.³²³ As depicted in Scheme 2, it is this synthetic step which paved the way to the design and synthesis of EDP-235 (85) and led to 14 distinct patents claiming many spiropyrrolidine series of SARS-CoV-2 M^pro inhibitors. Interestingly, this rearrangement⁴¹⁶ was previously used⁴¹⁷ in 1996 to prepare esters and nitrile derivatives somehow related to 154 and 155. History will tell if it was their evaluation on SARS-CoV-2 M^pro which was at the source of these strong inhibitors.

Scheme 2 Structures of compounds 150–152; oxidative rearrangement of compound 153 into 154 and 155.

Finally, in the following years some viral strains resistant to the currently available SARS-CoV-2 M^pro inhibitors will unfortunately emerge in the population^418–423 and these strains will likely compromise the corresponding drug efficacy. For that reason, as well as a price lowering effect, it is very important to have the widest possible range of efficient SARS-CoV-2 multiplication inhibitors so that a lack of cross-resistances between these drugs can be expected. In this regard, the possibility of a general/partial cross-resistance between all the covalent SARS-CoV-2 M^pro inhibitors currently used or developed today is a very relevant issue. In any case, any array of coronavirus-adapted antiviral drugs will be handy to address the next corona epidemic before specific vaccines are designed and mass-produced. Indeed, the recent major progress made with RNA-based vaccines is challenging MedChem and the much longer time usually required to provide a drug-based treatment. Past the next coronavirus pandemics, anticipating such challenges for other zoonotic diseases as well could be a good idea.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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