Immunoproteasome ?5i-Selective Dipeptidomimetic Inhibitors.

ABSTRACT: N,C-capped dipeptides belong to a class of noncovalent proteasome inhibitors. Herein we report that the insertion of a ?-amino acid into N,C-capped dipeptides markedly decreases their inhibitory potency against human constitutive proteasome ?5c, while maintaining potent inhibitory activity against human immunoproteasome ?5i, thereby achieving thousands-fold selectivity for ?5i over ?5c. Structure-activity relationship studies revealed that ?5c does not tolerate the ?-amino acid based dipeptidomimetics as does ?5i. 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.

SUBMITTER: Singh PK 

PROVIDER: S-EPMC5760267 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature