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

Article


Allardyce, D., Bell, C. and Loizidou, E. 2019. Argyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i. Chemical Biology and Drug Design. 94 (2), pp. 1556-1567. https://doi.org/10.1111/cbdd.13539
TypeArticle
TitleArgyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i
AuthorsAllardyce, D., Bell, C. and Loizidou, E.
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 β5i and β1i sites of the immunoproteasome over the β5c and β1c sites of the constitutive proteasome with nearly 20-fold selective inhibition of β1i over the homologous β1c. Molecular modelling attributes the β1i over β1c selectivity to the small hydrophobic S1 pocket of β1i and β5i over β5c 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.

Keywordsargyrin B; docking; immunoproteasome; non-competitive binding; selective inhibitors
PublisherWiley
JournalChemical Biology and Drug Design
ISSN1747-0277
Electronic1747-0285
Publication dates
Online06 Jun 2019
Print28 Jul 2019
Publication process dates
Deposited08 Apr 2019
Accepted31 Mar 2019
Output statusPublished
Accepted author manuscript
Copyright Statement

This is the peer reviewed version of the following article: Allardyce, DJ, Bell, CM, Loizidou, EZ. Argyrin B, a non‐competitive inhibitor of the human immunoproteasome exhibiting preference for β1i. Chem Biol Drug Des. 2019; 94: 1556– 1567. doi:10.1111/cbdd.13539, which has been published in final form at https://doi.org/10.1111/cbdd.13539. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Digital Object Identifier (DOI)https://doi.org/10.1111/cbdd.13539
Web of Science identifierWOS:000477776500012
LanguageEnglish
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