Abstract
The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as 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 for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.
Original language | English (US) |
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Pages (from-to) | 3491-3506 |
Number of pages | 16 |
Journal | Computational and Structural Biotechnology Journal |
Volume | 19 |
DOIs | |
State | Published - Jan 2021 |
Keywords
- ArgB
- ArgC
- ArgD
- ArgF
- FBDD
- Mycobacterium tuberculosis
ASJC Scopus subject areas
- Biotechnology
- Biophysics
- Structural Biology
- Biochemistry
- Genetics
- Computer Science Applications