Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?
Basic Information
ID: ALA4321793
Journal: J Med Chem
Title: Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?
Authors: Cianni L, Feldmann CW, Gilberg E, Gütschow M, Juliano L, Leitão A, Bajorath J, Montanari CA.
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.
CiteXplore: 31361135
DOI: 10.1021/acs.jmedchem.9b00683
Patent ID: ┄