Argyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i.

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 beta 5i and beta 1i sites of the immunoproteasome over the beta 5c and beta 1c sites of the constitutive proteasome with nearly 20-fold selective inhibition of beta 1i over the homologous beta 1c. Molecular modelling attributes the beta 1i over beta 1c selectivity to the small hydrophobic S1 pocket of beta 1i and beta 5i over beta 5c 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.