Hepatitis C virus (HCV) remains a major threat to public health despite the advent of direct acting antivirals (DAAs) targeting viral protease and RNA polymerase. Resistance development, as a natural outcome from attack by therapeutics, and the prohibitive cost of DAAs demand alternative and more powerful therapeutics. Our laboratory has been studying the mechanisms of HCV entry in the hopes of identifying novel cellular targets for antiviral development. Entry inhibitors targeting host functions will be particularly valuable in treating post-transplant hepatitis C, where one of the major unmet needs is the development of strategies to prevent re- infection of the liver graft after transplantation. During the previous funding period, we found that cell signaling proteins prohibitins 1 and 2 (PHB1/2) are essential pan-genomic HCV entry factors that function at a post- binding step. Although commonly known as mitochondrial inner membrane proteins, a fraction of endogenous PHB1 and 2 localize to the cell surface. Interestingly, plasma-membrane-associated PHBs are known for membrane targeting and activation of CRaf by Ras upon epidermal growth factor receptor (EGFR) activation. Targeting PHBs by rocaglamide (Roc-A), a natural compound that binds both PHB1/2, reduced cell surface PHB1/2, disrupted PHB-CRaf interaction, and inhibited HCV entry at low nanomolar concentrations. A subsequent screen of a collection of synthetic Roc-A derivatives indicated that the (-) Roc-A enantiomer is a more potent entry inhibitor than the (+) Roc-A enantiomer. Strikingly, the chiral, racemic version of a Roc-A derivative displayed improved potency and therapeutic index against HCV infection in cell culture. These findings open an unprecedented opportunity to dissect the HCV entry process and to translate basic research into antiviral development. In this competing renewal, we propose to dissect the master signaling pathway that coordinates HCV entry and optimize our lead compound for treating HCV infection. Accomplishing the project will significantly advance our understanding of HCV entry, and lead to a new class of entry inhibitors.

Public Health Relevance

The proposed research will not only provide mechanistic insight into prohibitin-mediated entry of hepatitis C virus (HCV), but will provide critical information on how to target prohibitin 1 and 2 for antiviral development. Completion of the project will lead to the development of a new class of anti-HCV therapeutics, adding more weapons to our much needed anti-HCV arsenal.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
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Sri International
Menlo Park
United States
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Peng, Hui; Ning, Huan; Wang, Qinghong et al. (2018) Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing TH2 cells through the Notch/Gata3 pathway. J Allergy Clin Immunol 142:582-594.e10
Lin, Shih-Chao; Kappes, Matthew A; Chen, Mei-Chun et al. (2017) Distinct susceptibility and applicability of MDCK derivatives for influenza virus research. PLoS One 12:e0172299
Li, Hongmei; He, Hui; Gong, Leyi et al. (2016) Short Communication: Preferential Killing of HIV Latently Infected CD4(+) T Cells by MALT1 Inhibitor. AIDS Res Hum Retroviruses 32:174-7
Liu, Shufeng; Zhao, Ting; Song, BenBen et al. (2016) Comparative Proteomics Reveals Important Viral-Host Interactions in HCV-Infected Human Liver Cells. PLoS One 11:e0147991
Liu, Shufeng; DeLalio, Leon J; Isakson, Brant E et al. (2016) AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus. Circ Res 119:1183-1189
Li, Hongmei; Wang, Tony T (2016) MCPIP1/regnase-I inhibits simian immunodeficiency virus and is not counteracted by Vpx. J Gen Virol 97:1693-8
Wei, Dahai; Li, Nan L; Zeng, Yanli et al. (2016) The Molecular Chaperone GRP78 Contributes to Toll-like Receptor 3-mediated Innate Immune Response to Hepatitis C Virus in Hepatocytes. J Biol Chem 291:12294-309
Huang, Shengping; Liu, Shufeng; Fu, Jia J et al. (2015) Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation. J Biol Chem 290:20782-92
Liu, Shufeng; Wang, Wenyu; Brown, Lauren E et al. (2015) A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway. EBioMedicine 2:1600-6
Liu, Baoming; Li, Nan L; Wang, Jie et al. (2014) Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus. J Virol 88:13821-35

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