Premium
Immunoproteasome β5i‐Selective Dipeptidomimetic Inhibitors
Author(s) -
Singh Pradeep K.,
Fan Hao,
Jiang Xiuju,
Shi Lei,
Nathan Carl F.,
Lin Gang
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600384
Subject(s) - proteasome , chemistry , cytotoxicity , in vitro , inhibitory postsynaptic potential , structure–activity relationship , amino acid , biochemistry , potency , pharmacology , stereochemistry , biology , neuroscience
N,C‐capped dipeptides belong to a class of noncovalent proteasome inhibitors. Herein we report that the insertion of a β‐amino acid into N,C‐capped dipeptides markedly decreases their inhibitory potency against human constitutive proteasome β5c, while maintaining potent inhibitory activity against human immunoproteasome β5i, thereby achieving thousands‐fold selectivity for β5i over β5c. Structure–activity relationship studies revealed that β5c does not tolerate the β‐amino acid based dipeptidomimetics as does β5i. In vitro, one such compound was found to inhibit human T cell proliferation. Compounds of this class may have potential as therapeutics for autoimmune and inflammatory diseases with less mechanism‐based cytotoxicity than agents that also inhibit the constitutive proteasome.