Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75
文献类型：期刊论文
| 作者 | Li BW1,2; Zhang FH2; Serrao E3; Chen H4; Sanchez TW3; Yang LM4; Neamati N3; Zheng YT4; Wang H[*]1; Long YQ[*]2 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2014 |
| 卷号 | 22期号:12页码:3146-3158 |
| 关键词 | Chelation Strand transfer LEDGF/p75 HIV-1 integrase inhibitors Flavonoid |
| 通讯作者 | huiwang@scnu.edu.cn ; yqlong@mail.shcnc.ac.cn |
| 合作状况 | 其它 |
| 英文摘要 | HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their beta-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50 = 0.826 mu g/mL) and high therapeutic index (TI > 242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low-to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains. |
| 资助信息 | The work in Y.-Q.L. laboratory was supported by National Nat- ural Science Foundation of China (81072527, 81325020, 81361120410 and 81123004), the work in N.N. laboratory was supported by funds from an NIH/NIAID (R21AI081610) grant, and the work in Y.-T.Z. laboratory was supported in part by the National Natural Science Foundation of China (81102483) and the Key Scientific and Technological Program of China (2009ZX09501-029, 2012ZX10001-006). |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000335912300009 |
| 公开日期 | 2014-10-15 |
| 源URL | [http://159.226.149.42:8088/handle/152453/8038]  |
| 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.School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China 2.CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China 3.Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA 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 | Li BW,Zhang FH,Serrao E,et al. Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2014,22(12):3146-3158. |
| APA | Li BW.,Zhang FH.,Serrao E.,Chen H.,Sanchez TW.,...&Long YQ[*].(2014).Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75.BIOORGANIC & MEDICINAL CHEMISTRY,22(12),3146-3158. |
| MLA | Li BW,et al."Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75".BIOORGANIC & MEDICINAL CHEMISTRY 22.12(2014):3146-3158. |
入库方式： OAI收割
来源：昆明动物研究所
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