Benzhydrylpiperazine compounds inhibit cholesterol-dependent cellular entry of hepatitis C virus.

Benzhydrylpiperazine compounds inhibit cholesterol-dependent cellular entry of hepatitis C virus. Antiviral Res. 2014 Jul 11; Authors: Chamoun-Emanuelli AM, Pécheur EI, Chen Z Abstract Hepatitis C virus (HCV) remains a serious global health problem that lacks an effective cure. Although the introduction of protease inhibitors to the current standard-of-care interferon/ribavirin therapy for HCV infection has improved sustained virological response of genotype 1-infected patients, these inhibitors exacerbate already problematic side effects. Thus, new HCV antivirals are urgently needed. Using a cell-protection screen previously developed in our laboratory, we evaluated 30,426 compounds for inhibitors of potentially any stage of the HCV life cycle and identified 49 new HCV inhibitors. The two most potent hits, hydroxyzine and chlorcyclizine, belong to the family of benzhydrylpiperazines and were found to inhibit the entry of cell culture-produced HCV with IC50 values of 19 and 2.3nM, respectively, and therapeutic indexes of >500 and >6500. Both compounds block HCV entry at a late stage of entry prior to viral fusion and their inhibitory activities are highly dependent on the host's cholesterol content. Both compounds are currently used in the clinic for treating allergy-related disorders and the reported peak plasma level (160nM) and estimated liver concentration (1.7μM) of hydroxyzine in humans are much higher than the molecule...
Source: Antiviral Research - Category: Virology Authors: Tags: Antiviral Res Source Type: research