Introduction to the themed collection on ‘Neglected tropical diseases’

For a very long time, neglected tropical diseases (NTDs) have not received as much attention as other diseases despite their severity and the fact that they currently affect one sixth of the world's population. NTDs largely affect the poor in tropical regions, who lack basic necessities of hygiene and sanitation and are frequently malnourished. The costs, lack of sustainable distribution networks, and poor adaptation to resource-poor settings of current therapies often make treatment a distant reality for those living in endemic regions around the world. The incredible toll NTDs have taken on global health is appalling and is a stark reminder of the dire need to eradicate NTDs. The WHO has therefore incorporated various programs, including improvement of sanitary conditions and access to affordable therapeutics. However, the most demanding and most challenging part of a mitigation program is often to find a potent, yet cost effective therapy well adapted to the needs of patients to support ‘A road map for NTDs 2021–2030’ and Sustainable Development Goals.¹

NTDs such as Chagas disease, leishmaniasis, human African trypanosomiasis, schistosomiasis, dengue, etc., are connected by a common lack of knowledge and investment in research and face inherent drug development challenges including drug resistance, drug ineffectiveness at all stages of the disease, extreme toxicity, and cost. A variety of novel approaches to tackle NTDs have been sought; these include the use of drug delivery vehicles like liposomes or nanoparticles, thereby reducing toxicity; using innovative bioinformatics methods for high throughput screening to find novel drug targets; and combinatorial therapies. In addition, improving absorption, distribution, metabolism and elimination (ADME) of previous and novel new drugs are also valuable approaches. The current situation with the COVID-19 pandemic has drawn the world's attention and so more than ever we need to be aware, write, talk and give due importance to NTDs so that patients are not forgotten. To this end, in this themed collection we highlight some of the most crucial work going on across the globe on leishmaniasis, Chagas disease, human African trypanosomiasis, dengue, and schistosomiasis.

Researchers have still not been able to identify any potential dengue fever (DENV) protease and polymerase inhibitors. Herein, Yokokawa provides a comprehensive review focusing upon the progress of phenotype-based inhibitors against dengue fever (DOI: 10.1039/D0MD00052C). The application of phenotype-based hit-to-lead chemistry optimization has proved to be quite a promising approach for the discovery of potential antivirals against DENV. Dziwornu et al. provide a temporal roadmap regarding the advances in chemotyping of potential chemical compounds in the field of human schistosomiasis (DOI: 10.1039/D0MD00062K). The literature mainly highlights in vitro and in vivo anti-schistosomal activities of chemical derivatives of praziquantel (PZQ), oxamniquine (OXA) and antimalarial drugs like artemisinins. Here the promising future of ureas, imidazoles, pyrazolopyrimidine-5-carboxamides, pyrimidopyrimidines and chalcones that could be potential leads is now discussed. Visceral leishmaniasis is another fatal protozoan disease in humans, leading to more than 20–30 000 deaths per year. In some regions it can also affect dogs, providing a further challenge for disease control. Due to the high skin parasite burden, dogs are the best urban reservoir for parasites and cause autochthonous human infections. Faral-Tello et al. describe the isolation of five clinical isoforms of L. infantum possibly responsible for the 2015 outbreak of canine visceral leishmaniasis in Uruguay (DOI: 10.1039/D0MD00073F). This study highlights that the newly isolated strains exhibit high growth rates, infectivity and resistance against available anti-leishmanial drugs like amphotericin B, both during their promastigote and amastigote stages. The strategic application of combination therapy can be promising for combating the development of drug resistance in leishmaniasis patients. Ahmed et al. experimentally validate the efficacy of single as well as combination treatments with compounds like the alkylphosphocholine analogues APC12 and APC14, miltefosine (MIL), ketoconazole (KTZ), and amphotericin B (AmpB) upon wild-type and drug-resistant L. mexicana promastigotes (DOI: 10.1039/D0MD00101E). The comparative analysis illustrates that targeting the sterol biosynthesis pathway using synergistic combination therapy can improve the efficacy against drug-resistant Leishmania when compared to monotherapy. Besides synthetic chemical inhibitors, discoveries of naturally derived anti-leishmanial leads are also blossoming. Anderson et al. describe the anti-leishmanial potency of hederagenin, a triterpenoid saponin isolated from the common ivy plant (DOI: 10.1039/D0MD00123F). Significant leishmanicidal activity of the compound, as well as its chemical derivatives, was obtained against axenic L. mexicana amastigotes. These could be pivotal contributions to the field of NTDs and these investigations support the target-blind screening of potential drug-like substances from natural resources against NTDs. Parthasarathy and Kalesh present a review on the applications within NTDs of mass spectrometry-based proteomics (DOI: 10.1039/D0MD00122H). They also highlight how the combination of synthetic chemistry/chemical probes and proteomic techniques (namely chemical proteomics) can provide important data on the mode of action and off-target effects of pharmacologically active molecules within parasite systems.

In summary, this themed collection highlights the development of synthetic and natural compounds for NTD therapy. It highlights emerging approaches that can be used to identify new targets, understand modes of action and provide tools to tackle drug resistance. It also further highlights some of the key challenges within the NTD research field, encouraging useful scientific discussions and introducing new researchers and their ideas and expertise to the area.

References

1. https://www.who.int/neglected_diseases/WHONTD-roadmap-2030/en/ .

---