Syder, A. J. et al. (2011) Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. Journal of Hepatology, 54(1), pp. 48-55. (doi: 10.1016/j.jhep.2010.06.024) (PMID:20932595)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Grove, Dr Joe |
| Authors: | Syder, A. J., Lee, H., Zeisel, M. B., Grove, J., Soulier, E., Macdonald, J., Chow, S., Chang, J., Baumert, T. F., McKeating, J. A., McKelvy, J., and Wong-Staal, F. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | Journal of Hepatology |
| Publisher: | Elsevier |
| ISSN: | 0168-8278 |
| ISSN (Online): | 1600-0641 |
| Published Online: | 21 August 2010 |
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