Targeting caseinolytic protease P and its AAA1 chaperone for tuberculosis treatment

Xin Xu; Laiying Zhang; Tao Yang; Zhiqiang Qiu; Lang Bai; Youfu Luo

doi:10.1016/j.drudis.2023.103508

Targeting caseinolytic protease P and its AAA1 chaperone for tuberculosis treatment

Drug Discov Today. 2023 Mar;28(3):103508. doi: 10.1016/j.drudis.2023.103508. Epub 2023 Jan 24.

Authors

Xin Xu¹, Laiying Zhang¹, Tao Yang², Zhiqiang Qiu¹, Lang Bai³, Youfu Luo⁴

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
² Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
³ Center of Infectious Diseases and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: pangbailang@163.com.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: luo_youfu@scu.edu.cn.

PMID: 36706830
DOI: 10.1016/j.drudis.2023.103508

Abstract

Caseinolytic protease P with its AAA1 chaperone, known as Mycobacterium tuberculosis (Mtb)ClpP1P2 proteolytic machinery, maintains protein homeostasis in Mtb cells and is essential for bacterial survival. It is regarded as an important biological target with the potential to address the increasingly serious issue of multidrug-resistant (MDR) TB. Over the past 10 years, many MtbClpP1P2-targeted modulators have been identified and characterized, some of which have shown potent anti-TB activity. In this review, we describe current understanding of the substrates, structure and function of MtbClpP1P2, classify the modulators of this important protein machine into several categories based on their binding subunits or pockets, and discuss their binding details; Such information provides insights for use in candidate drug research and development of TB treatments by targeting MtbClpP1P2 proteolytic machinery.

Keywords: TB treatment; caseinolytic protease P; targeted candidates.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents
Humans
Mycobacterium tuberculosis*
Tuberculosis* / therapy

Substances

Antitubercular Agents