Structure-Based Design and Synthesis of C-1- and C-4-Modified Analogs of Zanamivir as Neuraminidase Inhibitors
文献类型：期刊论文
| 作者 | Feng, Enguang2; Shin, Woo-Jin1; Zhu, Xuelian2; Li, Jian2; Ye, Deju2; Wang, Jiang2 ; Zheng, Mingyue2; Zuo, Jian-Ping2; No, Kyoung Tai1; Liu, Xian2
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2013-02-14 |
| 卷号 | 56期号:3页码:671-684 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm3009713 |
| 文献子类 | Article |
| 英文摘要 | In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 mu M against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 mu M, H5N1 IC50 = 0.012 mu M, H1N1 IC50 = 0.001 mu M). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t(1/2)) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents. |
| WOS关键词 | INFLUENZA-VIRUS NEURAMINIDASE ; AVIAN INFLUENZA ; ANTIINFLUENZA EVALUATION ; RATIONAL DESIGN ; HIGHLY POTENT ; ACTIVE-SITE ; DRUG DESIGN ; GS 4071 ; DERIVATIVES ; SIALIDASE |
| 资助项目 | National Basic Research Program of China[2009CB940903] ; National Basic Research Program of China[2012CB518000] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81025017] ; National S&T Major Projects[2012ZX09103-101-072] ; R&D Program of MKE/KEIT[10031969] ; MEST[2010-0001932] ; Korea Healthcare Technology R&D project, Ministry for Health, Welfare Family Affairs, Republic of Korea[A085105] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000315182100006 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277731]  |
| 专题 | 药物发现与设计中心 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 药物化学研究室 药理学第一研究室 |
| 通讯作者 | Liu, Hong |
| 作者单位 | 1.Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 120749, South Korea 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Feng, Enguang,Shin, Woo-Jin,Zhu, Xuelian,et al. Structure-Based Design and Synthesis of C-1- and C-4-Modified Analogs of Zanamivir as Neuraminidase Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(3):671-684. |
| APA | Feng, Enguang.,Shin, Woo-Jin.,Zhu, Xuelian.,Li, Jian.,Ye, Deju.,...&Liu, Hong.(2013).Structure-Based Design and Synthesis of C-1- and C-4-Modified Analogs of Zanamivir as Neuraminidase Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,56(3),671-684. |
| MLA | Feng, Enguang,et al."Structure-Based Design and Synthesis of C-1- and C-4-Modified Analogs of Zanamivir as Neuraminidase Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 56.3(2013):671-684. |
入库方式： OAI收割
来源：上海药物研究所
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