Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference**

Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference**. Bakali, J. E., Blaszczyk, M., Evans, J. C., Boland, J. A., McCarthy, W. J., Fathoni, I., Dias, M. V. B., Johnson, E. O., Coyne, A. G., Mizrahi, V., Blundell, T. L., Abell, C., & Spry, C. Angewandte Chemie International Edition, 62(17):e202300221, John Wiley & Sons, Ltd, apr, 2023.

Paper doi abstract bibtex

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD \textless 20 µM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.

@article{Bakali2023,
abstract = {The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD {\textless} 20 µM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.},
author = {Bakali, Jamal El and Blaszczyk, Michal and Evans, Joanna C. and Boland, Jennifer A. and McCarthy, William J. and Fathoni, Imam and Dias, Marcio V. B. and Johnson, Eachan O. and Coyne, Anthony G. and Mizrahi, Valerie and Blundell, Tom L. and Abell, Chris and Spry, Christina},
doi = {10.1002/ANIE.202300221},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bakali et al. - 2023 - Chemical validation of iMycobacterium tuberculosisi phosphopantetheine adenylyltransferase using fragment linking.pdf:pdf},
issn = {1521-3773},
journal = {Angewandte Chemie International Edition},
keywords = {Based,Coenzyme A,Drug Discovery,Enzymes,Fragment,OA,OA{\_}PMC,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {17},
pages = {e202300221},
pmid = {38515507},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference**}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202300221 https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202300221 https://onlinelibrary.wiley.com/doi/10.1002/anie.202300221},
volume = {62},
year = {2023}
}

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