Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase
文献类型：期刊论文
| 作者 | Long, YQ; Jiang, XH; Dayam, R; Sanchez, T; Shoemaker, R; Sei, S; Neamati, N |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2004-05-06 |
| 卷号 | 47期号:10页码:2561-2573 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm030559k |
| 文献子类 | Article |
| 英文摘要 | Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme as an important target for the development of therapeutics against HIV infection. In fact, S-1360, the first clinically used IN inhibitor containing a triazole ring as a bioisostere of a carboxylic acid moiety belongs to this class of compounds. To understand the role of divalent metal-chelating in the inhibition of IN (J. Med. Chem. 2002, 45, 56615670), we designed and synthesized a series of novel dimeric diketo-containing compounds with the notion that such dimeric compounds may simultaneously bind to two divalent metal ions on the active site of IN. We rationalized that the two diketo subunits separated by uniquely designed linkers can potentially chelate two metal ions that are either provided from one IN active site or two active sites juxtaposed together in a higher order tetramer. Herein, we show that all the new compounds are highly potent against purified IN with varied selectivity for strand transfer, and that some of the analogues exert potent inhibition of the cytopathic effect of HIV-1 in infected CEM cells. This study represents the first attempt to rationally target two divalent metal ions on the active site of IN and may have potential implications for the design of second generation diketoacid-containing class of inhibitors. |
| WOS关键词 | CATALYTIC DOMAIN ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; ESCHERICHIA-COLI ; TERMINAL DOMAINS ; STRAND TRANSFER ; PRIMARY TARGET ; DNA COMPLEX ; MUTANT ; CELLS |
| 资助项目 | PHS HHS[N01-C0-12400] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000221183800020 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/274078]  |
| 专题 | 药物化学研究室 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 | Long, YQ |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.NCI, Lab Antiviral Drug Mech, Screening Technol Branch, DTP,DCTD, Frederick, MD 21702 USA 3.Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA |
| 推荐引用方式 GB/T 7714 | Long, YQ,Jiang, XH,Dayam, R,et al. Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase[J]. JOURNAL OF MEDICINAL CHEMISTRY,2004,47(10):2561-2573. |
| APA | Long, YQ.,Jiang, XH.,Dayam, R.,Sanchez, T.,Shoemaker, R.,...&Neamati, N.(2004).Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase.JOURNAL OF MEDICINAL CHEMISTRY,47(10),2561-2573. |
| MLA | Long, YQ,et al."Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase".JOURNAL OF MEDICINAL CHEMISTRY 47.10(2004):2561-2573. |
入库方式： OAI收割
来源：上海药物研究所
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