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Citation

BibTex format

@article{Benns:2022:10.1038/s41564-022-01249-y,
author = {Benns, HJ and Storch, M and Falco, JA and Fisher, FR and Tamaki, F and Alves, E and Wincott, CJ and Milne, R and Wiedemar, N and Craven, G and Baragaña, B and Wyllie, S and Baum, J and Baldwin, GS and Weerapana, E and Tate, EW and Child, MA},
doi = {10.1038/s41564-022-01249-y},
journal = {Nat Microbiol},
title = {CRISPR-based oligo recombineering prioritizes apicomplexan cysteines for drug discovery.},
url = {http://dx.doi.org/10.1038/s41564-022-01249-y},
year = {2022}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Nucleophilic amino acids are important in covalent drug development yet underutilized as anti-microbial targets. Chemoproteomic technologies have been developed to mine chemically accessible residues via their intrinsic reactivity towards electrophilic probes but cannot discern which chemically reactive sites contribute to protein function and should therefore be prioritized for drug discovery. To address this, we have developed a CRISPR-based oligo recombineering (CORe) platform to support the rapid identification, functional prioritization and rational targeting of chemically reactive sites in haploid systems. Our approach couples protein sequence and function with biological fitness of live cells. Here we profile the electrophile sensitivity of proteinogenic cysteines in the eukaryotic pathogen Toxoplasma gondii and prioritize functional sites using CORe. Electrophile-sensitive cysteines decorating the ribosome were found to be critical for parasite growth, with target-based screening identifying a parasite-selective anti-malarial lead molecule and validating the apicomplexan translation machinery as a target for ongoing covalent ligand development.
AU - Benns,HJ
AU - Storch,M
AU - Falco,JA
AU - Fisher,FR
AU - Tamaki,F
AU - Alves,E
AU - Wincott,CJ
AU - Milne,R
AU - Wiedemar,N
AU - Craven,G
AU - Baragaña,B
AU - Wyllie,S
AU - Baum,J
AU - Baldwin,GS
AU - Weerapana,E
AU - Tate,EW
AU - Child,MA
DO - 10.1038/s41564-022-01249-y
PY - 2022///
TI - CRISPR-based oligo recombineering prioritizes apicomplexan cysteines for drug discovery.
T2 - Nat Microbiol
UR - http://dx.doi.org/10.1038/s41564-022-01249-y
UR - https://www.ncbi.nlm.nih.gov/pubmed/36266336
ER -

Contact

Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821