Immunoproteasome 5i-Selective Dipeptidomimetic Inhibitors

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. Invitro, one such compound was found to inhibit human Tcell 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.