Structure–Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides

The
immunoproteasome (i-20S) has emerged as a therapeutic target
for autoimmune and inflammatory disorders and hematological malignancies.
Inhibition of the chymotryptic β5i subunit of i-20S inhibits
T cell activation, B cell proliferation, and dendritic cell differentiation
in vitro and suppresses immune responses in animal models of autoimmune
disorders and allograft rejection. However, cytotoxicity to immune
cells has accompanied the use of covalently reactive β5i inhibitors,
whose activity against the constitutive proteasome (c-20S) is cumulative
with the time of exposure. Herein, we report a structure–activity
relationship study of a class of noncovalent proteasome inhibitors
with picomolar potencies and 1000-fold selectivity for i-20S over
c-20S. Furthermore, these inhibitors are specific for β5i over
the other five active subunits of i-20S and c-20S, providing useful
tools to study the functions of β5i in immune responses. The
potency of these compounds in inhibiting human T cell activation suggests
that they may have therapeutic potential.