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Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction

文献类型：期刊论文

作者Serrao, Erik1; Xu, Zhong-Liang2; Debnath, Bikash1; Christ, Frauke3; Debyser, Zeger3; Long, Ya-Qiu2; Neamati, Nouri1
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2013-10-01
卷号21期号:19页码:5963-5972
关键词HIV-1 Integrase LEDGF/p75 5-carbonyl-1H-Imidazole-4-carboxamide Protein-protein interaction Antiviral PDB ID code2B4J
ISSN号0968-0896
DOI10.1016/j.bmc.2013.07.047
文献子类Article
英文摘要Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase-LEDGF/p75 interaction in vitro. Following a structure-activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound's structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
WOS关键词SMALL-MOLECULE INHIBITORS ; DIKETO ACID PHARMACOPHORE ; INTEGRASE INHIBITORS ; ANTIRETROVIRAL THERAPY ; COMBINATION THERAPY ; BINDING-SITE ; LEDGF/P75 ; REPLICATION ; PROTEIN ; MULTIMERIZATION
资助项目NIH/NIAID[R21 AI081610] ; Campbell Foundation[00000000] ; National Natural Science Foundation of China[81072527] ; National Natural Science Foundation of China[81021062]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000324046600004
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/277446]  
专题药物化学研究室
通讯作者Long, Ya-Qiu
作者单位1.Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA;
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
3.Katholieke Univ Leuven, Div Mol Med, Lab Mol Virol & Gene Therapy, B-3000 Louvain, Flanders, Belgium
推荐引用方式
GB/T 7714		 Serrao, Erik,Xu, Zhong-Liang,Debnath, Bikash,et al. Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2013,21(19):5963-5972.
APA Serrao, Erik.,Xu, Zhong-Liang.,Debnath, Bikash.,Christ, Frauke.,Debyser, Zeger.,...&Neamati, Nouri.(2013).Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction.BIOORGANIC & MEDICINAL CHEMISTRY,21(19),5963-5972.
MLA Serrao, Erik,et al."Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction".BIOORGANIC & MEDICINAL CHEMISTRY 21.19(2013):5963-5972.

入库方式： OAI收割

来源：上海药物研究所

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