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Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase

文献类型：期刊论文

作者Du, Li1; Zhao, Ya-xue2; Yang, Liu-meng3; Zheng, Yong-tang3; Tang, Yun2; Shen, Xu1,2; Jiang, Hua-liang1,2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2008-10
卷号29期号:10页码:1261-1267
关键词HIV-1 integrase inhibitor surface plasma resonance molecular docking site-directed mutagenesis
ISSN号1671-4083
DOI10.1111/j.1745-7254.2008.00863.x
文献子类Article
英文摘要Aim: To characterize the functional and pharmacological features of a symmetrical 1-pyrrolidineacetamide, N,N'-(methylene-di-4,1-phenylene) bis-1-pyrrolidineacetamide, as a new anti-HIV compound which could competitively inhibit HIV-1 integrase (IN) binding to viral DNA. Methods: A surface plasma resonance (SPR)-based competitive assay was employed to determine the compound's inhibitory activity, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell assay was used to qualify the antiviral activity. The potential binding sites were predicted by molecular modeling and determined by site-directed mutagenesis and a SPR binding assay. Results: 1-pyrrolidineacetamide, N,N'-(methylene-di-4,1-phenylene) bis-1-pyrrolidineacetamide could competitively inhibit IN binding to viral DNA with a 50% inhibitory concentration (IC50) value of 7.29 +/- 0.68 mu mol/L as investigated by SPR-based investigation. Another antiretroviral activity assay showed that this compound exhibited inhibition against HIV-1(IIIB) replication with a 50% effective concentration (EC50) value of 40.54 mu mol/L in C8166 cells, and cytotoxicity with a cytotoxic concentration value of 173.84 mu mol/L in mock-infected C8166 cells. Molecular docking predicted 3 potential residues as 1-pyrrolidineacetamide, N,N'-(methylene-di-4,1-phenylene)bis-1-pyrrolidineacetamide binding sites. The importance of 3 key amino acid residues (Lys 103, Lys 173, and Thr 174) involved in the binding was further identified by site-directed mutagenesis and a SPR binding assay. Conclusion: This present work identified a new anti-HIV compound through a new IN-binding site which is expected to supply new potential drug-binding site information for HIV-1 integrase inhibitor discovery and development.
WOS关键词IMMUNODEFICIENCY-VIRUS INTEGRASE ; FORCE-FIELD ; INHIBITORS ; PROTEIN ; DOCKING ; DOMAIN ; DNA ; IDENTIFICATION ; ORGANIZATION ; REPLICATION
资助项目National Natural Science Foundation of China[30525024] ; National Natural Science Foundation of China[20472095] ; National Natural Science Foundation of China[20572023] ; Shanghai Pujiang Program[05PJ14034] ; Shanghai Key Basic Research Project[06JC14080] ; Shanghai Key Basic Research Project[05JC14092] ; State Key Program of Basic Research of China[2004CB58905] ; State Key Program of Basic Research of China[2006AA09Z447] ; Chinese Academy of Sciences[KSCX2-YW-R-18]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:3370801
WOS记录号WOS:000259937500017
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272784]  
专题药理学第三研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Shen, Xu
作者单位1.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res,Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
2.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;
3.Chinese Acad Sci, Lab Mol Immunopharmacol, Key Lab Anim Models & Human Dis Mech, Kunming Inst Zool, Kunming 650223, Peoples R China
推荐引用方式
GB/T 7714		 Du, Li,Zhao, Ya-xue,Yang, Liu-meng,et al. Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase[J]. ACTA PHARMACOLOGICA SINICA,2008,29(10):1261-1267.
APA Du, Li.,Zhao, Ya-xue.,Yang, Liu-meng.,Zheng, Yong-tang.,Tang, Yun.,...&Jiang, Hua-liang.(2008).Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase.ACTA PHARMACOLOGICA SINICA,29(10),1261-1267.
MLA Du, Li,et al."Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase".ACTA PHARMACOLOGICA SINICA 29.10(2008):1261-1267.

入库方式： OAI收割

来源：上海药物研究所

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