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.

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

“…To alleviate safety concerns, Ebola pseudoparticles (EBOVpp), i.e., Ebola glycoprotein (GP) assembled onto retroviral core particles, were used to screen a triterpenoid library consisting of hundreds of chemicals. Vesicular stomatitis virus (VSV) GP and WSN influenza envelope hemagglutinin (HA)/neuraminidase (NA) protein pseudoparticles were tested in parallel to exclude toxic and non-specific effects 11,13 . We identified a panel of triterpenoid compounds that inhibited the EBOVpp to different extents, which were strongly related to their structures, but did not inhibit VSV and WSN (Fig.…”

“…As the viral envelope was the only difference between EBOVpp and the VSV and WSN pseudoviruses 19 , we determined whether EBOV GP was the potential target of the triterpenoid lead Y11 by a series of time-of-addition experiments 11,13,19 , including pretreatment of the viruses, pretreatment of the cells, and pre-attachment, postattachment and post-entry assays conducted in parallel, as previously reported (Supplementary Fig. 2a).…”

“…Very recently, analogues/derivatives of OA and echinocystic acid (EA), an OA-type triterpene, were found to exert a variety of inhibitory activities, strongly related to their structures, against influenza virus and HCV infection [11][12][13] . Further investigations suggested that these triterpenoid leads might bind to viral fusion proteins, including hemagglutinin (HA2) of influenza, E2 of HCV and GP41 of HIV, thereby disrupting viral entry into the host cells 11,13,14 . Whether the observed antiviral aspects of triterpenoids extend to other viruses and translate into a shared mechanism that can chemically antagonize the fusion of viruses with cellular membranes remains a topic of ongoing investigation.…”

Crystal structure of benzyl-2-oxo-oleanic acid, C37H52O4

“…It has been reported to exhibits pharmacological activities, such as anti-tumor, anti-viral, anti-HIV and anti-HCV activities [1,2]. Because of its wide biological activities and its potential applications, the extraction, synthesis and biological activity of oleanic acid and its derivatives have attracted much attention [3][4][5][6][7].Inthis paper, we report the crystal structure of the title compound, whose synthetic protocolhas been alreadyreported elsewhere [7]. In the molecule of thetitle compound (Fig.…”

Strategies to Preclude Hepatitis C Virus Entry

“…The boronic acid (BA)-modified nanoparticles were also found to suppress HCV entry in a way that acted similar to lectins [113], with the incorporation of lipid nanocapsule (BA-LNC) techniques enhancing their stability and solubility [114]. Chemically modified oleanolic acid, a triterpene compound originally extracted from Dipsacus asperoides, was found able to interrupt the E2-CD81 interaction by binding to E2 [115].…”