Project description:The emergence of drug-resistant viruses against nucleot(s)ide analogs (NAs), which are the main treatment for chronic hepatitis B virus (HBV) infection, has become a problem. To discover novel anti-HBV compounds with a low risk of emergence of drug-resistant viruses, we performed screening of a G protein-coupled receptor-associated compound library and identified Rimonabant as a candidate. Transcriptome analysis of Rimonabant-treated primary hepatocytes by RNA sequencing revealed that the transcriptional activity of HNF4α, which is known to stimulate viral RNA synthesis, was depressed.
Project description:Infection with hepatitis E virus (HEV) represents a global problem, with over 20 million people infected annually. No specific antiviral drugs are available for treating HEV infection, necessitating the development of novel targeted therapeutics. Here, we report that the N-methyl-D-aspartate receptor (NMDAR) antagonist ifenprodil, a clinically approved drug used to treat idiopathic pulmonary fibrosis (IPF), is an HEV inhibitor in liver-derived cells. In vitro investigation demonstrates that ifenprodil suppresses viral protein expression in a dose-dependent manner in human hepatoma cells by inhibiting early stages of viral infection. We also found that ifenprodil modulates host cell intrinsic biological processes distinct from virus-induced innate immunity, inhibiting HEV RNA accumulation in primary human hepatocytes. Finally, the inhibitory effect of ifenprodil in vivo was also tested in rabbits challenged with the HEV-3ra CHN-BJ-R14 strain. Fecal virus shedding was below the limit of detection in two animals for both ribavirin-treated and ifenprodil-treated rabbits compared to vehicle-treated control animals. Our data demonstrate that ifenprodil is an effective anti-HEV compound with potential as a therapeutic candidate for the treatment of HEV infection.