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Selective inhibition of cysteine-dependent enzymes by bioorthogonal tethering

Spear, Luke A., Huang, Yang, Chen, Jinghao, Nödling, Alexander R., Virdee, Satpal and Tsai, Yu-Hsuan 2022. Selective inhibition of cysteine-dependent enzymes by bioorthogonal tethering. Journal of Molecular Biology 10.1016/j.jmb.2022.167524

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Abstract

A general approach for the rapid and selective inhibition of enzymes in cells using a common tool compound would be of great value for research and therapeutic development. We previously reported a chemogenetic strategy that addresses this challenge for kinases, relying on bioorthogonal tethering of a pan inhibitor to a target kinase through a genetically encoded non-canonical amino acid. However, pan inhibitors are not available for many enzyme classes. Here, we expand the scope of the chemogenetic strategy to cysteine-dependent enzymes by bioorthogonal tethering of electrophilic warheads. For proof of concept, selective inhibition of two E2 ubiquitin-conjugating enzymes, UBE2L3 and UBE2D1, was demonstrated in biochemical assays. Further development and optimization of this approach should enable its use in cells as well as other cysteine-dependent enzymes, facilitating the investigation of their cellular function and validation as therapeutic targets.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Chemistry
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
Publisher: Elsevier
ISSN: 0022-2836
Funders: EPSRC (EP/N509449/1), BBSRC (BB/ P003982/1)
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Date of First Compliant Deposit: 16 March 2022
Date of Acceptance: 28 February 2022
Last Modified: 16 Mar 2022 13:15
URI: https://orca.cardiff.ac.uk/id/eprint/148169

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