Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase

	Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase
	Hu, QH; Liu, RJ; Fang, ZP; Zhang, J; Ding, YY; Tan, M; Wang, M; Pan, W; Zhou, HC; Wang, ED
刊名	SCIENTIFIC REPORTS
	2013
卷号	3 期号:1 页码:2475-2475
通讯作者	Zhou, HC (reprint author), Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China.,hczhou@sjtu.edu.cn ; edwang@sibcb.ac.cn
英文摘要	Streptococcus pneumoniae causes bacterial pneumonia with high mortality and morbidity. The emergency of multidrug-resistant bacteria threatens the treatment of the disease. Leucyl-tRNA synthetase (LeuRS) plays an essential role in cellular translation and is an attractive drug target for antimicrobial development. Here we report the compound ZCL039, a benzoxaborole-based derivative of AN2690, as a potent anti-pneumococcal agent that inhibits S. pneumoniae LeuRS (SpLeuRS) activity. We show using kinetic, biochemical analyses combined with the crystal structure of ZCL039-AMP in complex with the separated SpLeuRS editing domain, that ZCL039 binds to the LeuRS editing active site which requires the presence of tRNALeu, and employs an uncompetitive inhibition mechanism. Further docking models establish that ZCL039 clashes with the eukaryal/archaeal specific insertion I4ae helix within editing domains. These findings demonstrate the potential of benzoxaboroles as effective LeuRS inhibitors for pneumococcus infection therapy, and provide future structure-guided drug design and optimization.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	ESCHERICHIA-COLI ; CP1 DOMAIN ; CRYSTAL-STRUCTURE ; ANTIFUNGAL AGENT ; QUALITY-CONTROL ; AMINOACYLATION ; RESISTANCE ; INHIBITORS ; ANTIBIOTICS ; TRANSLATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000323243800003
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/492]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Hu, QH,Liu, RJ,Fang, ZP,et al. Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase[J]. SCIENTIFIC REPORTS,2013,3(1):2475-2475.
APA	Hu, QH.,Liu, RJ.,Fang, ZP.,Zhang, J.,Ding, YY.,...&Wang, ED.(2013).Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase.SCIENTIFIC REPORTS,3(1),2475-2475.
MLA	Hu, QH,et al."Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase".SCIENTIFIC REPORTS 3.1(2013):2475-2475.