Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy.
J Med Chem
; 67(14): 11917-11936, 2024 Jul 25.
Article
em En
| MEDLINE
| ID: mdl-38958057
ABSTRACT
Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC50 = 1.19 µM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Proteína Fosfatase 2C
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Mycobacterium tuberculosis
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Antituberculosos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China