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学科主题药学
Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors
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
2013-06-13
DOI10.1021/jm301910a
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
资助者National Basic Research Program of China (973 Program) ; National Natural Science Foundation of China ; National Basic Research Program of China (973 Program) ; National Natural Science Foundation of China
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
资助者National Basic Research Program of China (973 Program) ; National Natural Science Foundation of China ; National Basic Research Program of China (973 Program) ; National Natural Science Foundation of China
WOS记录号WOS:000320640900010
Citation statistics
Cited Times:46[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/50632
Collection北京大学药学院
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
GB/T 7714
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.
APA Yu, Fei.,Wang, Qi.,Zhang, Zhen.,Peng, Yiyun.,Qiu, Yunyan.,...&Zhou, Demin.(2013).Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,56(11),4300-4319.
MLA Yu, Fei,et al."Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 56.11(2013):4300-4319.
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