Cysteine proteases as therapeutic targets:does selectivity matter? A systematic review of calpain an

来源 :Acta Pharmaceutica Sinica B | 被引量 : 0次 | 上传用户:kaka43210
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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. 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. Reactive, active-site cysteine ​​provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor selectivity often families with 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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