TY - JOUR
T1 - Cysteine proteases as therapeutic targets
T2 - Does selectivity matter? A systematic review of calpain and cathepsin inhibitors
AU - Siklos, Marton
AU - BenAissa, Manel
AU - Thatcher, Gregory R.J.
N1 - Publisher Copyright:
© 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Calpain
KW - Cathepsin
KW - Cysteine protease
KW - Enzyme inhibitors
KW - Neurodegeneration
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U2 - 10.1016/j.apsb.2015.08.001
DO - 10.1016/j.apsb.2015.08.001
M3 - Review article
AN - SCOPUS:84976225303
SN - 2211-3835
VL - 5
SP - 506
EP - 519
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 6
ER -