title: Development of oleanane-type triterpenes as a new class of HCV entry inhibitors.
abstract: 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 μM. 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 μM. 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 ~5-fold (54a, IC50 0.3 μM). Formation of a triterpene dimer via a linker bearing triazole (70) dramatically increased its potency with IC50 at ~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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Peng
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Qiu
authors.forename: Yongying
authors.initials: Y
authors.lastname: Shi
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Sulong
authors.initials: S
authors.lastname: Xiao
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Huang
authors.forename: Linyi
authors.initials: L
authors.lastname: Zhu
authors.forename: Kunbo
authors.initials: K
authors.lastname: Chen
authors.forename: Chuanke
authors.initials: C
authors.lastname: Zhao
authors.forename: Chuanling
authors.initials: C
authors.lastname: Zhang
authors.forename: Maorong
authors.initials: M
authors.lastname: Yu
authors.forename: Dian
authors.initials: D
authors.lastname: Sun
authors.forename: Lihe
authors.initials: L
authors.lastname: Zhang
authors.forename: Demin
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology; D057809:HEK293 Cells; D053878:Hemolytic Agents / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003603:Cytotoxins; D053878:Hemolytic Agents; D009828:Oleanolic Acid; C022999:echinocystic acid