Covalent Cysteine Protease Inhibitors in Disease: How to Optimize their Pharmacokinetic Properties and Selectivity Profiles
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Abstract
Cysteine proteases have become promising targets for drug development, particularly in light of recent advancements in treating COVID-19 with nirmatrelvir, a covalent reversible inhibitor of the SARS-CoV-2 main protease (Mpro). Given the wide range of cysteine proteases found in various organisms, the potential applications of covalent cysteine protease inhibitors to address parasitic, viral, cancerous, and autoimmune diseases are numerous. However, achieving effective drug delivery to target sites and minimizing off-target effects requires the development of selective scaffolds with optimal physicochemical properties.
In this dissertation, I present the development of selective (F-)vinylsulfon(at)e-based cysteine protease inhibitors with beneficial pharmacokinetic properties, focusing on three target proteases from the cathepsin family as examples: Trypanosoma brucei cathepsin L (TbCatL, rhodesain), Schistosoma mansoni cathepsin B1 (SmCB1), and human cathepsin S (CatS).
Molecular docking studies combined with enzyme and phenotypic assays were crucial for the inhibitor design and evaluation. The results of these studies have been essential in guiding the development of inhibitors with enhanced efficacy and selectivity. Moreover, valuable insights into the biodistribution and metabolism of several compounds have been obtained through in vivo studies as well as in vitro metabolism studies. To further improve efficacy, targeted drug delivery strategies were explored in one of the projects.