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J Hepatol. 2011 Jan;54(1):48-55. doi: 10.1016/j.jhep.2010.06.024. Epub 2010 Aug 21.

Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors.

Author information

1
iTherX Pharmaceuticals, Inc., San Diego, CA 92191-0530, USA.

Abstract

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.

PMID:
20932595
DOI:
10.1016/j.jhep.2010.06.024
[Indexed for MEDLINE]

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