Discovering covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4 (PADI4) using mRNA-display with a genetically encoded electrophilic warhead
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Author(s)
Mathiesen, IR
Calder, EDD
Kunzelmann, S
Walport, LJ
Type
Journal Article
Abstract
Covalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target. Here we demonstrate the direct discovery of covalent cyclic peptides using encoded libraries containing a weakly electrophilic cysteine-reactive fluoroamidine warhead. We combine direct incorporation of the warhead into peptide libraries using the flexible in vitro translation system with a peptide selection approach that identifies only covalent target binders. Using this approach, we identify potent and selective covalent inhibitors of the peptidyl arginine deiminase, PADI4 or PAD4, that react exclusively at the active site cysteine. We envisage this approach will enable covalent peptide inhibitor discovery for a range of related enzymes and expansion to alternative warheads in the future.
Date Issued
2024-12-19
Date Acceptance
2024-12-04
ISSN
2399-3669
Publisher
Nature Portfolio
Journal / Book Title
Communications Chemistry
Volume
7
Copyright Statement
© The Author(s) 2024
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons licence and your intended use is not permitted
by statutory regulation or exceeds the permitted use, you will need to
obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons licence and your intended use is not permitted
by statutory regulation or exceeds the permitted use, you will need to
obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
License URI
Identifier
https://www.nature.com/articles/s42004-024-01388-9
Publication Status
Published
Article Number
304
Date Publish Online
2024-12-19