Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?

Journal of Medicinal Chemistry
Lorenzo CianniCarlos A Montanari

Abstract

Cysteine proteases are important targets for the discovery of novel therapeutics for many human diseases. From parasitic diseases to cancer, cysteine proteases follow a common mechanism, the formation of an encounter complex with subsequent nucleophilic reactivity of the catalytic cysteine thiol group toward the carbonyl carbon of a peptide bond or an electrophilic group of an inhibitor. Modulation of target enzymes occurs preferably by covalent modification, which imposes challenges in balancing cross-reactivity and selectivity. Given the resurgence of irreversible covalent inhibitors, can they impair off-target effects or are reversible covalent inhibitors a better route to selectivity? This Perspective addresses how small molecule inhibitors may achieve selectivity for different cathepsins, cruzain, rhodesain, and falcipain-2. We discuss target- and ligand-based designs emphasizing repurposing inhibitors from one cysteine protease to others.

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Citations

Nov 5, 2019·Physical Chemistry Chemical Physics : PCCP·Jerônimo LameiraCarlos A Montanari
Mar 13, 2020·PLoS Neglected Tropical Diseases·Lorenzo CianniCarlos A Montanari
Dec 9, 2020·Future Medicinal Chemistry·Rafael da Fonseca LameiroCarlos Alberto Montanari
Dec 1, 2020·Bioorganic & Medicinal Chemistry·Lorenzo CianniAnwar Shamim
Mar 4, 2020·Journal of Chemical Information and Modeling·José Rogério A SilvaCarlos A Montanari
Mar 4, 2020·Journal of Medicinal Chemistry·Bala C ChennaThomas D Meek
May 15, 2020·Biochimica Et Biophysica Acta. Proteins and Proteomics·Julian BreidenbachMichael Gütschow
Jul 8, 2020·Journal of Chemical Information and Modeling·Jorge Enrique Hernández GonzálezPedro Geraldo Pascutti
Apr 24, 2021·Journal of Medicinal Chemistry·Naoya KitamuraJun Wang
Jun 8, 2021·RSC Medicinal Chemistry·Vinicius BonattoCarlos A Montanari
Jul 22, 2021·Organic & Biomolecular Chemistry·Kelton A Schleyer, Lina Cui
Jan 17, 2020·Journal of Chemical Information and Modeling·Clauber H S da CostaCarlos A Montanari
Aug 31, 2021·Journal of Chemical Information and Modeling·Vinícius BonattoCarlos A Montanari

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