Drug Discovery Efforts to Identify Novel Treatments for Neglected
Tropical Diseases - Cysteine Protease Inhibitors

Maude      Giroud; Bernd      Kuhn; Wolfgang      Haap
doi:10.2174/0109298673249097231017051733
Abstract

Background: Neglected tropical diseases are a severe burden for mankind, affecting an increasing number of people around the globe. Many of those diseases are caused by protozoan parasites in which cysteine proteases play a key role in the parasite’s pathogenesis.
Objective: In this review article, we summarize the drug discovery efforts of the research community from 2017 - 2022 with a special focus on the optimization of small molecule cysteine protease inhibitors in terms of selectivity profiles or drug-like properties as well as in vivo studies. The cysteine proteases evaluated by this methodology include Cathepsin B1 from Schistosoma mansoni, papain, cruzain, falcipain, and rhodesain.
Methods: Exhaustive literature searches were performed using the keywords “Cysteine Proteases” and “Neglected Tropical Diseases” including the years 2017 - 2022. Overall, approximately 3’000 scientific papers were retrieved, which were filtered using specific keywords enabling the focus on drug discovery efforts.
Results and Conclusion: Potent and selective cysteine protease inhibitors to treat neglected tropical diseases were identified, which progressed to pharmacokinetic and in vivo efficacy studies. As far as the authors are aware of, none of those inhibitors reached the stage of active clinical development. Either the inhibitor’s potency or pharmacokinetic properties or safety profile or a combination thereof prevented further development of the compounds. More efforts with particular emphasis on optimizing pharmacokinetic and safety properties are needed, potentially by collaborations of academic and industrial research groups with complementary expertise. Furthermore, new warheads reacting with the catalytic cysteine should be exploited to advance the research field in order to make a meaningful impact on society.
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DOI https://dx.doi.org/10.2174/0109298673249097231017051733	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Drug Discovery Efforts to Identify Novel Treatments for Neglected Tropical Diseases - Cysteine Protease Inhibitors

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