A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis
© 2021 The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Computational and structural biotechnology journal - 19(2021) vom: 01., Seite 3491-3506 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gupta, Pooja [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 14.02.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.csbj.2021.06.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Gupta, Pooja |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2021 The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ASU, asymmetric unit | |
| 650 | 4 | |a ArgB | |
| 650 | 4 | |a ArgC | |
| 650 | 4 | |a ArgD | |
| 650 | 4 | |a ArgF | |
| 650 | 4 | |a DSF, Differential scanning fluorimetry | |
| 650 | 4 | |a FBDD | |
| 650 | 4 | |a FBDD, Fragment-based drug discovery | |
| 650 | 4 | |a ITC, Isothermal titration calorimetry | |
| 650 | 4 | |a Mycobacterium tuberculosis | |
| 650 | 4 | |a NMR, Nuclear magnetic resonance | |
| 650 | 4 | |a SPR, Surface plasmon resonance | |
| 650 | 4 | |a TB, tuberculosis | |
| 700 | 1 | |a Thomas, Sherine E |e verfasserin |4 aut | |
| 700 | 1 | |a Zaidan, Shaymaa A |e verfasserin |4 aut | |
| 700 | 1 | |a Pasillas, Maria A |e verfasserin |4 aut | |
| 700 | 1 | |a Cory-Wright, James |e verfasserin |4 aut | |
| 700 | 1 | |a Sebastián-Pérez, Víctor |e verfasserin |4 aut | |
| 700 | 1 | |a Burgess, Ailidh |e verfasserin |4 aut | |
| 700 | 1 | |a Cattermole, Emma |e verfasserin |4 aut | |
| 700 | 1 | |a Meghir, Clio |e verfasserin |4 aut | |
| 700 | 1 | |a Abell, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Coyne, Anthony G |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobs, William R |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Blundell, Tom L |e verfasserin |4 aut | |
| 700 | 1 | |a Tiwari, Sangeeta |e verfasserin |4 aut | |
| 700 | 1 | |a Mendes, Vítor |e verfasserin |4 aut | |
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