A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis.

Gupta, P.; Thomas, S. E.; Cory-Wright, J.; Sebastián-Pérez, V.; Burgess, A.; Cattermole, E.; Meghir, C.; Abell, C.; Coyne, A. G.; Jacobs, W. R.; Blundell, T. L.; Tiwari, S.; Mendes, V.

doi:10.1101/2021.03.12.435067

bioRxiv · 10.1101/2021.03.12.435067

A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis.

Gupta, P.·Thomas, S. E.·Cory-Wright, J.·Sebastián-Pérez, V.·Burgess, A.·Cattermole, E.·Meghir, C.·Abell, C.·Coyne, A. G.·Jacobs, W. R.·Blundell, T. L.·Tiwari, S.·Mendes, V.

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Abstract

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine, appears to be attractive target for anti-Tuberculosis (TB) drug discovery. Starvation of M. tuberculosis deleted for either argB or argF genes led to rapid sterilization of these strains in mice while Chemical inhibition of ArgJ with Pranlukast was also found to clear chronic M. tuberculosis infection in animal models. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is explored using a fragment-based approach. We reveal several hits for these enzymes validated with biochemical and biophysical assays, and X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential of more enzymes in this pathway to be targeted with dedicated drug discovery programmes.

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Gupta, P., Thomas, S. E., Cory-Wright, J., Sebastián-Pérez, V., Burgess, A., Cattermole, E., Meghir, C., Abell, C., Coyne, A. G., Jacobs, W. R., Blundell, T. L., Tiwari, S., Mendes, V.. 2021-03-12. A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis.. https://doi.org/10.1101/2021.03.12.435067

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