中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy

文献类型：期刊论文

作者Yu, Zhipeng5; Liang, Yi Chu3,4; Berton, Stefania3; Liu, Liping1,2; Zou, Jiaqi5; Chen, Lu1,2; Xu, Zhongliang1,2; Luo, Cheng1,2; Sun, Jim3,4; Yang, Weibo1,2,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-03
卷号67期号:14页码:11917-11936
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00513
通讯作者Sun, Jim(jim.sun@ubc.ca) ; Yang, Weibo(yweibo@simm.ac.cn)
英文摘要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 mu M), 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.
WOS关键词DERIVATIVES ; POTENT ; INHIBITORS ; IDENTIFICATION ; DISCOVERY ; BINDING
资助项目NSFC[82373708] ; NSFC[22171275] ; Shanghai Academic/Technology Research Leader[23XD1424400] ; Canadian Institutes of Health Research[PJT-162424] ; Canadian Institutes of Health Research[PPE-185827] ; National Sanitarium Association Scholar's Program ; Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center on Systems and Personalized Pharmacology[SIMMUO201801/201902/202001/202102] ; CGS-D scholarship from the Natural Sciences and Engineering Research Council of Canada
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001263165900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312291]  
专题中国科学院上海药物研究所
通讯作者Sun, Jim; Yang, Weibo
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada
4.Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z3, Canada
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Zhipeng,Liang, Yi Chu,Berton, Stefania,et al. Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(14):11917-11936.
APA Yu, Zhipeng.,Liang, Yi Chu.,Berton, Stefania.,Liu, Liping.,Zou, Jiaqi.,...&Yang, Weibo.(2024).Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy.JOURNAL OF MEDICINAL CHEMISTRY,67(14),11917-11936.
MLA Yu, Zhipeng,et al."Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy".JOURNAL OF MEDICINAL CHEMISTRY 67.14(2024):11917-11936.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。