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Siklos, Marton; BenAissa, Manel; Thatcher, Gregory R J
Acta pharmaceutica Sinica. B, 11/2015, Volume: 5, Issue: 6Journal Article
Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and cathepsins.The reactive,active-site cysteine provides specificity for many inhibitor designs over other families of proteases,such as aspartate and serine;however,a)inhibitor strategies often use covalent enzyme modification,and b)obtaining selectivity within families of cysteine proteases and their isozymes is problematic.This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders;the latter focus providing an interesting query for the contemporary assumptions that irreversible,covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.
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