Journal
JOURNAL OF HEPATOLOGY
Volume 54, Issue 1, Pages 48-55Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2010.06.024
Keywords
HCV entry inhibitors; SR-BI antagonists
Categories
Funding
- European Union [ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Superieur-FEDER-2009-Hepato-Regio-Net]
- Else-Kroner-Fresenius Stiftung, Bad Homburg, Germany [P17/07//A83/06]
- Medical Research Council, UK
- Wellcome Trust
- Medical Research Council [G0801976, G0400802] Funding Source: researchfish
- MRC [G0400802, G0801976] Funding Source: UKRI
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI036214] Funding Source: NIH RePORTER
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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. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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