Selective Inhibition of the Immunoproteasome by Structure‐Based Targeting of a Non‐catalytic Cysteine

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.