title: A novel inhibitor of human La protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pharmacy, First People's Hospital Affiliated with Shanghai JiaoTong University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Huang
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Chen
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Gao-Lin
authors.initials: GL
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D014584:User-Computer Interface; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C574674:La protein, human; D010750:Phosphoproteins