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

	Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase
	Du L 2; Zhao YX 3; Yang LM 4; Zheng YT 4; Tang Y[]3; Shen X[]2,3; Jiang HL 2,3; ytang234@ecust.edu.cn ; xshen@mail.shcnc.ac.cn
	2008
发表期刊	ACTA PHARMACOLOGICA SINICA
ISSN	1671-4083
卷号	29 期号:10 页码:1261-1267
合作性质	其它
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.
关键词	Hiv-1 Integrase Inhibitor Surface Plasma Resonance Molecular Docking Site-directed Mutagenesis
资助者	This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18). ; This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18). ; This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18). ; This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18).
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收录类别	SCI
语种	英语
资助者	This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18). ; This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18). ; This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18). ; This work was financially supported by the National Natural Science Foundation of China (No 30525024, 20472095, and 20572023), Shanghai Pujiang Program (No 05PJ14034), Shanghai Key Basic Research Project (No 06JC14080 and 05JC14092), the State Key Program of Basic Research of China (No 2004CB58905 and 2006AA09Z447), and a grant from the Chinese Academy of Sciences (No KSCX2-YW-R-18).
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/4623
专题	科研部门_分子免疫药理学（郑永唐）科研部门_动物模型与人类重大疾病机理重点实验室
通讯作者	ytang234@ecust.edu.cn; xshen@mail.shcnc.ac.cn
作者单位	1.** 2.Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China 3.School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China 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	Du L,Zhao YX,Yang LM,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 L.,Zhao YX.,Yang LM.,Zheng YT.,Tang Y[*].,...&xshen@mail.shcnc.ac.cn.(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 L,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.

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