Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors

Background and Aims

ITX 5061 is a clinical stage small molecule compound that promotes high-density lipoprotein (HDL) levels in animals and patients by targeting the scavenger receptor BI protein pathway. Since SR-BI is a known co-receptor for HCV infection, we evaluated these compounds for their effects on HCV entry.

Methods

We obtained ITX 5061 and related compounds to characterize their interaction with SR-BI and effects on HCV entry and infection.

Results

We confirmed that a tritium-labeled compound analog (ITX 7650) binds cells expressing SR-BI, and both ITX 5061 and ITX 7650 compete for HDL-mediated lipid transfer in an SR-BI dependent manner. Both molecules inhibit HCVcc and HCVpp infection of primary human hepatocytes and/or human hepatoma cell lines and have minimal effects on HCV RNA replication. Kinetic studies suggest that the compounds act at an early post-binding step.

Conclusions

These results suggest that the ITX compounds inhibit HCV infection with a mechanism of action distinct from other HCV therapies under development. Since ITX 5061 has already been evaluated in over 280 patients with good pharmacokinetic and safety profiles, it warrants proof-of-concept clinical studies in HCV infected patients.

Abbreviations: ITX, iTherx, SR-BI, scavenger receptor class B, type I, VSVGpp, vesicular stomatitis virus G protein, pseudotyped particles, HCV, hepatitis C virus, HCVcc, cell culture derived HCV, HCVpp, HCV pseudo-particles, p38 MAPK, p38 mitogen-activated protein kinase, UGT1A1, uridine diphosphate glucuronosyltransferase 1, polypeptide A1

Keywords: HCV entry inhibitors, SR-BI antagonists