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
Type | Article |
---|---|
Title | Argyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i |
Authors | Allardyce, 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. |
Keywords | argyrin B; docking; immunoproteasome; non-competitive binding; selective inhibitors |
Publisher | Wiley |
Journal | Chemical Biology and Drug Design |
ISSN | 1747-0277 |
Electronic | 1747-0285 |
Publication dates | |
Online | 06 Jun 2019 |
28 Jul 2019 | |
Publication process dates | |
Deposited | 08 Apr 2019 |
Accepted | 31 Mar 2019 |
Output status | Published |
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 identifier | WOS:000477776500012 |
Language | English |
https://repository.mdx.ac.uk/item/8835y
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