Affiliation:
1. Pharma Research and Early Development pRED, Medicinal Chemistry, Switzerland
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 plays 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 activities such as 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.
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.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry