Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Cain, R.; Salimaraj, R.; Punekar, A. S.; Bellini, D.; Fishwisk, C. W. G.; Czapleski, L.; Scott, D. J.; Harris, G.; Dowson, C. G.; Lloyd, A. J.; Roper, D. I.

doi:10.1101/586255

bioRxiv · 10.1101/586255

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Cain, R.·Salimaraj, R.·Punekar, A. S.·Bellini, D.·Fishwisk, C. W. G.·Czapleski, L.·Scott, D. J.·Harris, G.·Dowson, C. G.·Lloyd, A. J.·Roper, D. I.

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Abstract

Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.

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Cain, R., Salimaraj, R., Punekar, A. S., Bellini, D., Fishwisk, C. W. G., Czapleski, L., Scott, D. J., Harris, G., Dowson, C. G., Lloyd, A. J., Roper, D. I.. 2019-03-22. Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase. https://doi.org/10.1101/586255

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