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学科主题: 药学
题名:
Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors
作者: Yu, Fei1; Wang, Qi1,2; Zhang, Zhen1; Peng, Yiyun1; Qiu, Yunyan1; Shi, Yongying1; Zheng, Yongxiang1; Xiao, Sulong1; Wang, Han1; Huang, Xiaoxi1; Zhu, Linyi1; Chen, Kunbo1; Zhao, Chuanke1; Zhang, Chuanling1; Yu, Maorong1; Sun, Dian3,4; Zhang, Lihe1; Zhou, Demin1
刊名: JOURNAL OF MEDICINAL CHEMISTRY
发表日期: 2013-06-13
DOI: 10.1021/jm301910a
卷: 56, 期:11, 页:4300-4319
收录类别: SCI ; IC
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Medicinal
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: ANTI-HIV ACTIVITY ; HEPATITIS-C ; CRATAEGUS-SINAICA ; ACID-DERIVATIVES ; VIRUS-INFECTION ; OLEANOLIC ACID ; MORONIC ACID ; AIDS AGENTS ; PROANTHOCYANIDINS ; FLAVONOIDS
英文摘要:

Development of hepatitis C virus (HCV) entry inhibitors represents an emerging approach that satisfies a tandem mechanism for use with other inhibitors in a multifaceted cocktail. By screening Chinese herbal extracts, oleanolic acid (OA) was found to display weak potency to inhibit HCV entry with an IC50 of 10 mu M. Chemical exploration of this triterpene compound revealed its pharmacophore requirement for blocking HCV entry, rings A, B, and E, are conserved while ring D is tolerant of some modifications. Hydroxylation at C-16 significantly enhanced its potency for inhibiting HCV entry with IC50 at 1.4 mu M. Further modification by conjugation of this new lead with a disaccharide at 28-COOH removed the undesired hemolytic effect and, more importantly, increased its potency by similar to 5-fold (54a, IC50 0.3 mu M). Formation of a triterpene dimer via a linker bearing triazole (70) dramatically increased its potency with IC50 at similar to 10 nM. Mechanistically, such functional triterpenes interrupt the interaction between HCV envelope protein E2 and its receptor CD81 via binding to E2, thus blocking virus and host cell recognition. This study establishes the importance of triterpene natural products as new leads for the development of potential HCV entry inhibitors.

语种: 英语
所属项目编号: 2010CB12300 ; 81101239 ; 20932001 ; 91029711 ; 20852001
项目资助者: National Basic Research Program of China (973 Program) ; National Natural Science Foundation of China
WOS记录号: WOS:000320640900010
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/50632
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, Beijing 100191, Peoples R China
3.Chinese Acad Med Sci, Inst Med Plant Dev, Beijing 100094, Peoples R China
4.Peking Union Med Coll, Beijing 100094, Peoples R China

Recommended Citation:
Yu, Fei,Wang, Qi,Zhang, Zhen,et al. Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(11):4300-4319.
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