Abstract
Diacylglycerol acyltransferases (DGATs) play a critical role in the biosynthesis of endogenous triglycerides (TGs) and formation of lipid droplets (LDs) in the liver. In particular, one member of DGATs, DGAT-1 was reported to be an essential host factor for the efficient production of hepatitis C virus (HCV) particles. By utilizing our previously characterized three different groups of twelve DGAT inhibitors, we found that one of the DGAT inhibitors, a 2-((4-adamantylphenoxy) methyl)-N-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxam (10j) is a potent suppressor of both HCV genome replication and particle production. 10j was able to induce inhibition of these two critical viral functions in a mutually separate manner. Abrogation of the viral genome replication by 10j led to a significant reduction in the viral protein expression as well. Interestingly, we found that its antiviral effect did not depend on the reduction of TG biosynthesis by 10j. This suggests that the inhibitory activity of 10j against DGATs may not be directly related with its antiviral action.
Highlights
Chronic hepatitis C virus (HCV) infection is responsible for several inflammatory liver diseases such as liver cirrhosis and hepatocellular carcinoma [1]
Since all of viral NS proteins play an essential role in the viral RNA genome replication, targeting their specific functions has been proven as an effective strategy to develop different kinds of anti-HCV therapeutics
We found that one of pan Diacylglycerol acyltransferases (DGATs) inhibitors, a 2-{[4-(adamant-1yl) phenoxy]methyl)-N-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamide (10j) possesses an antagonizing effect on both HCV genome replication and particle production and in a simultaneous manner
Summary
Chronic hepatitis C virus (HCV) infection is responsible for several inflammatory liver diseases such as liver cirrhosis and hepatocellular carcinoma [1]. HCV, a member of the Flaviviridae family, is a virus with a single-stranded RNA genome of positive polarity [2]. Upon entering hepatocytes via several liver-specific receptors, HCV expresses a single polyprotein composed of ≈3000 amino acids through a cap-independent translation of its RNA genome (≈9600 base pairs). E2) and six non-structural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) [3,4]. Since all of viral NS proteins play an essential role in the viral RNA genome replication, targeting their specific functions has been proven as an effective strategy to develop different kinds of anti-HCV therapeutics.
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