A novel inhibitor of human La protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation

PLoS One. 2012;7(4):e36363. doi: 10.1371/journal.pone.0036363. Epub 2012 Apr 27.

Abstract

Background: Over 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.

Aims: This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression.

Methods: A 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.

Results: 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. 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.

Conclusions: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Drug Evaluation, Preclinical
  • Hep G2 Cells
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / genetics
  • Hepatitis B virus / physiology
  • Humans
  • Models, Molecular
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Conformation
  • User-Computer Interface*
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • La protein, human
  • Phosphoproteins