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Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors

Syder, Andrew J and Lee, Haekyung and Zeisel, Mirjam B and Grove, Joe and Soulier, Eric and Macdonald, James and Chow, Stephine and Chang, Julia and Baumert, Thomas and McKeating, Jane A and McKelvy, Jeffrey and Wong-Staal, Flossie (2010) Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. Journal of hepatology. (In Press)

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URL of Published Version: http://dx.doi.org/10.1016/j.jhep.2010.06.024

Identification Number/DOI: 10.1016/j.jhep.2010.06.024

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.

Type of Work:Article
Date:2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:R Medicine (General)
QR355 Virology
QR180 Immunology
QR Microbiology
Institution:University of Birmingham
Copyright Holders:European Association for the Study of the Liver.
ID Code:499
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