ABSTRACT
Inhibitors of the proteasome have found broad therapeutic applications; however, they show severe toxicity due to the abundance of proteasomes in healthy cells. In contrast, inhibitors of the immunoproteasome, which is upregulated during disease states, are less toxic and have increased therapeutic potential including against autoimmune disorders. In this project, we report argyrin B, a natural product cyclic peptide to be a reversible, non-competitive inhibitor of the immunoproteasome. Argyrin B showed selective inhibition of the ß5i and ß1i sites of the immunoproteasome over the ß5c and ß1c sites of the constitutive proteasome with nearly 20-fold selective inhibition of ß1i over the homologous ß1c. Molecular modelling attributes the ß1i over ß1c selectivity to the small hydrophobic S1 pocket of ß1i and ß5i over ß5c to site-specific amino acid variations that enable additional bonding interactions and stabilization of the binding conformation. These findings facilitate the design of immunoproteasome selective and reversible inhibitors that may have a greater therapeutic potential and lower toxicity.