Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75

doi:10.1016/j.bmc.2014.04.016

	Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75
	Li, Bo-Wen 1,3; Zhang, Feng-Hua 1; Serrao, Erik 2; Chen, Huan 4; Sanchez, Tino W.2; Yang, Liu-Meng 4; Neamati, Nouri 2; Zheng, Yong-Tang 4; Wang, Hui 3; Long, Ya-Qiu 1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2014-06-15
卷号	22 期号:12 页码:3146-3158
关键词	HIV-1 integrase inhibitors Flavonoid Chelation Strand transfer LEDGF/p75
ISSN号	0968-0896
DOI	10.1016/j.bmc.2014.04.016
文献子类	Article
英文摘要	HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their beta-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50 = 0.826 mu g/mL) and high therapeutic index (TI > 242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low-to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains. (C) 2014 Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[81072527] ; National Natural Science Foundation of China[81325020] ; National Natural Science Foundation of China[81361120410] ; National Natural Science Foundation of China[81123004] ; National Natural Science Foundation of China[81102483] ; NIH/NIAID[R21AI081610] ; Key Scientific and Technological Program of China[2009ZX09501-029] ; Key Scientific and Technological Program of China[2012ZX10001-006]
WOS关键词	MULTIDRUG RESISTANCE ; BUTYL DICARBONATE ; CHELATION ; RALTEGRAVIR ; ALCOHOLS ; ETHERS ; DOMAIN ; CELLS ; QSAR
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000335912300009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277023]
专题	药物化学研究室
通讯作者	Wang, Hui
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Medica, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA; 3.S China Normal Univ, Sch Chem & Environm, Guangzhou 510006, Guangdong, Peoples R China; 4.Chinese Acad Sci, Kunming Inst Zool, Lab Mol Immunopharmacol, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Peoples R China
推荐引用方式 GB/T 7714	Li, Bo-Wen,Zhang, Feng-Hua,Serrao, Erik,et al. Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2014,22(12):3146-3158.
APA	Li, Bo-Wen.,Zhang, Feng-Hua.,Serrao, Erik.,Chen, Huan.,Sanchez, Tino W..,...&Long, Ya-Qiu.(2014).Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75.BIOORGANIC & MEDICINAL CHEMISTRY,22(12),3146-3158.
MLA	Li, Bo-Wen,et al."Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75".BIOORGANIC & MEDICINAL CHEMISTRY 22.12(2014):3146-3158.