Q1 · MEDICINE
Article
Author: Chang, Julia ; Grove, Joe ; MacDonald, James ; Zeisel, Mirjam B. ; Lee, Haekyung ; Baumert, Thomas F. ; Syder, Andrew J. ; McKeating, Jane A. ; Chow, Stephine ; Soulier, Eric ; McKelvy, Jeffrey ; Wong-Staal, Flossie
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.