Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors
Caseinolytic protease P (ClpP) responsible for the proteolysis of damaged or misfolded proteins plays a critical role in proteome homeostasis. MtbClpP1P2, a ClpP enzyme complex, is required for survival in Mycobacterium tuberculosis, and it is therefore considered as a promising target for the development of antituberculosis drugs. Here, we discovered that cediranib and some of its derivatives are potent MtbClpP1P2 inhibitors and suppress M. tuberculosis growth. Protein pull-down and loss-of-function assays validated the in situ targeting of MtbClpP1P2 by cediranib and its active derivatives. Structural and mutational studies revealed that cediranib binds to MtbClpP1P2 by binding to an allosteric pocket at the equatorial handle domain of the MtbClpP1 subunit, which represents a unique binding mode compared to other known ClpP modulators. These findings provide us insights for rational drug design of antituberculosis therapies and implications for our understanding of the biological activity of MtbClpP1P2.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 24 vom: 28. Dez., Seite 16597-16614 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Yang [VerfasserIn] |
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| Links: |
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| Themen: |
Bacterial Proteins |
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| Anmerkungen: |
Date Completed 29.12.2023 Date Revised 01.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c01054 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM365796484 |
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| 520 | |a Caseinolytic protease P (ClpP) responsible for the proteolysis of damaged or misfolded proteins plays a critical role in proteome homeostasis. MtbClpP1P2, a ClpP enzyme complex, is required for survival in Mycobacterium tuberculosis, and it is therefore considered as a promising target for the development of antituberculosis drugs. Here, we discovered that cediranib and some of its derivatives are potent MtbClpP1P2 inhibitors and suppress M. tuberculosis growth. Protein pull-down and loss-of-function assays validated the in situ targeting of MtbClpP1P2 by cediranib and its active derivatives. Structural and mutational studies revealed that cediranib binds to MtbClpP1P2 by binding to an allosteric pocket at the equatorial handle domain of the MtbClpP1 subunit, which represents a unique binding mode compared to other known ClpP modulators. These findings provide us insights for rational drug design of antituberculosis therapies and implications for our understanding of the biological activity of MtbClpP1P2 | ||
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| 700 | 1 | |a Zhao, Ninglin |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yuanzheng |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Baozhu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jiangnan |e verfasserin |4 aut | |
| 700 | 1 | |a Sui, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jiasheng |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Zhiqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xuelian |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Jumei |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Lang |e verfasserin |4 aut | |
| 700 | 1 | |a Bao, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Youfu |e verfasserin |4 aut | |
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