Abstract
BackgroundOver 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy.AimsThis study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression.MethodsA multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells.ResultsOf the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P<0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression.ConclusionsOur findings suggest that anti-HBV activity of HBSC-11 may be mediated by a reduction in hLa levels. In addition, our data suggest the potential clinical use of hLa inhibitors, such as HBSC-11, for treating HBV infection.
Highlights
More than 350 million people worldwide are chronically infected by the hepatitis B virus (HBV), increasing their risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma [1]
Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P,0.05
Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation
Summary
More than 350 million people worldwide are chronically infected by the hepatitis B virus (HBV), increasing their risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma [1]. Protein hLa is a 47 kDa phosphoprotein predominantly localized in the nucleus, and was originally identified as a major target of the autoimmune response in patients suffering from the autoimmune diseases Sjogren’s syndrome and systemic lupus erythematosus [6]. Since it has been characterized as a conserved RNA-binding protein that interacts with oligouridylate stretches in the RNA [7]. Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy
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