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

CORC > 昆明动物研究所 > 昆明动物研究所 > 动物模型与人类重大疾病机理重点实验室 > 分子免疫药理学

	Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75
	Li BW 1,2; Zhang FH 2; Serrao E 3; Chen H 4; Sanchez TW 3; Yang LM 4; Neamati N 3; Zheng YT 4; Wang H[]1; Long YQ[]2
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2014
卷号	22 期号:12 页码:3146-3158
关键词	Chelation Strand transfer LEDGF/p75 HIV-1 integrase inhibitors Flavonoid
通讯作者	huiwang@scnu.edu.cn ; yqlong@mail.shcnc.ac.cn
合作状况	其它
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.
收录类别	SCI
资助信息	The work in Y.-Q.L. laboratory was supported by National Nat- ural Science Foundation of China (81072527, 81325020, 81361120410 and 81123004), the work in N.N. laboratory was supported by funds from an NIH/NIAID (R21AI081610) grant, and the work in Y.-T.Z. laboratory was supported in part by the National Natural Science Foundation of China (81102483) and the Key Scientific and Technological Program of China (2009ZX09501-029, 2012ZX10001-006).
语种	英语
WOS记录号	WOS:000335912300009
公开日期	2014-10-15
内容类型	期刊论文
源URL	[http://159.226.149.42:8088/handle/152453/8038]
专题	昆明动物研究所_分子免疫药理学昆明动物研究所_动物模型与人类重大疾病机理重点实验室
作者单位	1.School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China 2.CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China 3.Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA 4.Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
推荐引用方式 GB/T 7714	Li BW,Zhang FH,Serrao E,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 BW.,Zhang FH.,Serrao E.,Chen H.,Sanchez TW.,...&Long YQ[*].(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 BW,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.