Journal article
Covalent Inhibition by a Natural Product-Inspired Latent Electrophile
DP Byun, J Ritchie, Y Jung, R Holewinski, HR Kim, R Tagirasa, J Ivanic, CM Weekley, MW Parker, T Andresson, E Yoo
Journal of the American Chemical Society | AMER CHEMICAL SOC | Published : 2023
DOI: 10.1021/jacs.3c00598
Abstract
Strategies to target specific protein cysteines are critical to covalent probe and drug discovery. 3-Bromo-4,5-dihydroisoxazole (BDHI) is a natural product-inspired, synthetically accessible electrophilic moiety that has previously been shown to react with nucleophilic cysteines in the active site of purified enzymes. Here, we define the global cysteine reactivity and selectivity of a set of BDHI-functionalized chemical fragments using competitive chemoproteomic profiling methods. Our study demonstrates that BDHIs capably engage reactive cysteine residues in the human proteome and the selectivity landscape of cysteines liganded by BDHI is distinct from that of haloacetamide electrophiles. Gi..
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Awarded by National Institutes of Health
Funding Acknowledgements
The authors gratefully thank the staff members at the CCR-Frederick Biophysics Resource (BR) and Flow Cytometry Core Facility for their assistance, technical consultation, and instrument maintenance. The authors also thank Jordan Meier and Martin Schnermann for the critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, the Center for Cancer Research (ZIABC011961). This project was also funded in part under contract No. HHSN261200800001E. Part of this work was carried out on the MX1 and MX2 beamlines at the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organization, and made use of the Australian Cancer Research Foundation detector on the MX2 beamline. The authors thank the beamline staff for their assistance. The authors acknowledge the use of the Mass Spectrometry and Proteomics Facility, Bio21 Institute, The University of Melbourne. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is acknowledged. MWP is a National Health and Medical Research Council (NHMRC) of Australia Investigator (APP1117183).