A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway

•Cellular proteins prohibitins 1 and 2 are essential HCV entry factors that function at a post-binding step.•The natural compound Roc-A potently blocks HCV infection by disrupting prohibitins-CRaf interaction•The Roc-A derivative, aglaroxin C, displays improved potency and therapeutic index towards HCV infectionCurrent FDA-approved HCV drugs all target viral proteins. We now demonstrate that a group of small molecules, the rocaglates, potently block HCV entry at low nanomolar concentrations. Roc-A inhibits HCV entry by disrupting the important interaction between two pan-genomic HCV entry factors, PHB1 and 2, and the signaling molecule CRaf. Overall, Roc-A and related rocaglates represent a new class of compounds that hold significant therapeutic promise in treating HCV infection.

Identification of novel drug targets and affordable therapeutic agents remains a high priority in the fight against chronic hepatitis C virus (HCV) infection. Here, we report that the cellular proteins prohibitin 1 (PHB1) and 2 (PHB2) are pan-genotypic HCV entry factors functioning at a post-binding step. While predominantly found in mitochondria, PHBs localize to the plasma membrane of hepatocytes through their transmembrane domains and interact with both EGFR and CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 and 2, reduced cell surface PHB1 and 2, disrupted PHB-CRaf interaction, and inhibited HCV entry at low nanomolar concentrations. A structure-activity analysis of 32 synthetic Roc-A analogs indicated that the chiral, racemic version of aglaroxin C, a natural product biosynthetically related to Roc-A, displayed improved potency and therapeutic index against HCV infection. This study reveals a new class of HCV entry inhibitors that target the PHB1/2-CRaf pathway.

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