2. Academic Validation
  3. Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy

Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy

  • J Med Chem. 2024 Jul 25;67(14):11917-11936. doi: 10.1021/acs.jmedchem.4c00513.
Zhipeng Yu 1,  Yi Chu Liang 2 3,  Stefania Berton 3,  Liping Liu 4 5,  Jiaqi Zou 1,  Lu Chen 4 5,  Zhongliang Xu 4 5,  Cheng Luo 4 5,  Jim Sun 2 3,  Weibo Yang 4 5 6 1
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
  • 2 Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • 3 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
  • 4 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 38958057 DOI: 10.1021/acs.jmedchem.4c00513
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.

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