The development of small-molecule modulators for ClpP protease activity

doi:10.1039/c6mb00644b

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	The development of small-molecule modulators for ClpP protease activity
	Ye, Fei 1; Li, Jiahui 2; Yang, Cai-Guang2
刊名	MOLECULAR BIOSYSTEMS
	2017
卷号	13 期号:1 页码:23-31
ISSN号	1742-206X
DOI	10.1039/c6mb00644b
文献子类	Review
英文摘要	The global spread of antibiotic resistance among important human pathogens emphasizes the need to find new antibacterial drugs with a novel mode of action. The ClpP protease has been shown to demonstrate its pivotal importance to both the survival and the virulence of pathogenic bacteria during host infection. Deregulating ClpP activity either through overactivation or inhibition could lead to antibacterial activity, declaiming the dual molecular mechanism for small-molecule modulation. Recently, natural products acyldepsipeptides (ADEPs) have been identified as a new class of antibiotics that activate ClpP to a dysfunctional state in the absence of cognate ATPases. ADEPs in combination with rifampicin eradicate deep-seated mouse biofilm infections. In addition, several non-ADEP compounds have been identified as activators of the ClpP proteolytic core without the involvement of ATPases. These findings indicate a general principle for killing dormant cells, the activation and corruption of the ClpP protease, rather than through conventional inhibition. Deletion of the clpP gene reduced the virulence of Staphylococcus aureus, thus making it an ideal antivirulence target. Multiple inhibitors have been developed in order to attenuate the production of extracellular virulence factors of bacteria through covalent modifications on serine in the active site or disruption of oligomerization of ClpP. Interestingly, due to the unusual composition and activation mechanism of ClpP in Mycobacterium tuberculosis, mycobacteria are killed by ADEPs through inhibition of ClpP activity rather than overactivation. In this short review, we will summarize recent progress in the development of small molecules modulating ClpP protease activity for both antibiotics and antivirulence.
资助项目	Public Projects of Zhejiang Province[2015C33159] ; Zhejiang Province Natural Science Foundation[LQ14H300003] ; National Natural Science Foundation of China[81402849] ; National Natural Science Foundation of China[21172234] ; Institute for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120154016]
WOS关键词	CYCLIC ACYLDEPSIPEPTIDE ANTIBIOTICS ; SITU CLICK CHEMISTRY ; AAA PLUS PROTEASE ; STAPHYLOCOCCUS-AUREUS ; CRYSTAL-STRUCTURE ; BETA-LACTONES ; LISTERIA-MONOCYTOGENES ; MYCOBACTERIUM-TUBERCULOSIS ; ANTIBACTERIAL ACTIVITY ; DEPENDENT PROTEASES
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000391697500002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275751]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Yang, Cai-Guang
作者单位	1.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Biol Chem Lab, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Ye, Fei,Li, Jiahui,Yang, Cai-Guang. The development of small-molecule modulators for ClpP protease activity[J]. MOLECULAR BIOSYSTEMS,2017,13(1):23-31.
APA	Ye, Fei,Li, Jiahui,&Yang, Cai-Guang.(2017).The development of small-molecule modulators for ClpP protease activity.MOLECULAR BIOSYSTEMS,13(1),23-31.
MLA	Ye, Fei,et al."The development of small-molecule modulators for ClpP protease activity".MOLECULAR BIOSYSTEMS 13.1(2017):23-31.