Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors.
J Med Chem
; 66(24): 16597-16614, 2023 12 28.
Article
en En
| MEDLINE
| ID: mdl-38088921
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Mycobacterium tuberculosis
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2023
Tipo del documento:
Article