Spear, Luke A., Huang, Yang, Chen, Jinghao, Nödling, Alexander R., Virdee, Satpal and Tsai, Yu-Hsuan ORCID: https://orcid.org/0000-0003-0589-5088 2022. Selective inhibition of cysteine-dependent enzymes by bioorthogonal tethering. Journal of Molecular Biology 434 , 167524. 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 |
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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) |
Related URLs: | |
Date of First Compliant Deposit: | 16 March 2022 |
Date of Acceptance: | 28 February 2022 |
Last Modified: | 18 May 2023 22:27 |
URI: | https://orca.cardiff.ac.uk/id/eprint/148169 |
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