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Development of oleanane-type triterpenes as a new class of HCV entry inhibitors.

Journal of medicinal chemistry (2013-05-15)
Fei Yu, Qi Wang, Zhen Zhang, Yiyun Peng, Yunyan Qiu, Yongying Shi, Yongxiang Zheng, Sulong Xiao, Han Wang, Xiaoxi Huang, Linyi Zhu, Kunbo Chen, Chuanke Zhao, Chuanling Zhang, Maorong Yu, Dian Sun, Lihe Zhang, Demin Zhou
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Oleanolic acid, ≥97%
Supelco
Oleanolic acid, analytical standard
Oleanolic acid, primary reference standard