Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference
| Autor: | Tom L. Blundell, Christina Spry, William J. McCarthy, Michal Blaszczyk, Joanna C. Evans, Chris Abell, Marcio Vinicius Bertacine Dias, Jennifer Boland, Anthony G. Coyne, Valerie Mizrahi, Jamal El Bakali |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
CRISPR interference Tuberculosis biology Coenzyme A Active site medicine.disease biology.organism_classification Mycobacterium tuberculosis chemistry.chemical_compound Enzyme chemistry Biosynthesis Biochemistry medicine biology.protein Phosphopantetheine adenylyltransferase |
| DOI: | 10.1101/2020.09.04.280388 |
| Popis: | 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 the first 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 < 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.Abstract Figure |
| Databáze: | OpenAIRE |
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