Clinically applied proteasome inhibitors induce cell death by concomitant
blockage of constitutive and immunoproteasomes. In contrast, selective
immunoproteasome inhibition is less cytotoxic and has the potential to modulate
chronic inflammation and autoimmune diseases. In this study, we rationally
designed decarboxylated peptides that covalently target a non-catalytic cysteine
of the immunoproteasome subunit β5i with α-chloroacetamide-containing
sidechains. The enhanced isoform specificity decreased cytotoxic effects and the
compound suppressed the production of inflammatory cytokines. Structure-based
optimization led to over 150-fold selectivity for subunit β5i over β5c. This
new compound class provides a promising starting point for the development of
selective immunoproteasome inhibitors as potential anti-inflammatory agents.
