中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction

文献类型:期刊论文

作者Zhang FH1; Debnath B2; Zheng YT3; Neamati N[*]2; Long YQ[*]1; Xu ZL1; Yang LM3; Song LR1
刊名European Journal of Medicinal Chemistry
出版日期2017
卷号125期号:X页码:1051-1063
关键词3-Hydroxypicolinamide Allosteric inhibitor Dimerization HIV-1 integrase LEDGF/p75
通讯作者neamati@umich.edu ; yqlong@simm.ac.cn
合作状况其它
英文摘要Currently, three HIV-1 integrase (IN) active site-directed inhibitors are in clinical use for the treatment of HIV infection. However, emergence of drug resistance mutations have limited the promise of a long-term cure. As an alternative, allosteric inhibition of IN activity has drawn great attention and several of such inhibitors are under early stage clinical development. Specifically, inhibitors of IN and the cellular cofactor LEDGF/p75 remarkably diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Distinct from the extensively studied 2-(quinolin-3-yl) acetic acid or 1H-indol-3-yl-2-hydroxy-4-oxobut-2-enoic acid chemotypes, this study discloses a new class of selective IN-LEDGF/p75 inhibitors without the carboxylic acid functionality. More significantly, 3-hydroxypicolinamides also show low micromolar inhibition against IN dimerization, providing novel dual IN inhibitors with in vitro therapeutically selective antiviral effect for further development. Finally, our shape-based ROCS pharmacophore model of the 3-hydroxypicolinamide class of compounds provides a new insight into the binding mode of these novel IN-LEDGF/p75 inhibitors.
资助信息The work in Long Laboratory was supported by the National Natural Science Foundation of China (81325020, 81361120410, 81321092 and 81123004) and the work in Neamati Laboratory was supported by the National Institutes of Health (NIH/NIAID grant R21 AI081610).
收录类别SCI
语种英语
源URL[http://159.226.149.26:8080/handle/152453/10627]  
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.CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
2.Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2800, USA
3.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
Zhang FH,Debnath B,Zheng YT,et al. Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction[J]. European Journal of Medicinal Chemistry,2017,125(X):1051-1063.
APA Zhang FH.,Debnath B.,Zheng YT.,Neamati N[*].,Long YQ[*].,...&Song LR.(2017).Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction.European Journal of Medicinal Chemistry,125(X),1051-1063.
MLA Zhang FH,et al."Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction".European Journal of Medicinal Chemistry 125.X(2017):1051-1063.

入库方式: OAI收割

来源:昆明动物研究所

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