Fasiglifam is a selective partial agonist of
G-protein-coupled receptor 40 (GPR40), which was developed for the treatment of
type 2 diabetes mellitus. However, the clinical development of
fasiglifam was voluntarily terminated during phase III clinical trials due to adverse liver effects.
Fasiglifam showed an inhibitory effect on
sodium taurocholate cotransporting polypeptide (NTCP) in human and rat hepatocytes. Recently, NTCP was reported to be a functional receptor for human hepatitis B virus (HBV)
infections. Therefore, in this study, we hypothesised that
fasiglifam would be a good candidate for a novel HBV entry inhibitor, and its effects were evaluated by using NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and human hepatocytes (PXB cells) obtained from PXB mice. Pre-treatment with
fasiglifam at a concentration of 30 μM prior to HBV
infection significantly suppressed supernatant HBV
DNA levels after HBV
infection in NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and PXB cells.
Fasiglifam did not suppress supernatant HBV
DNA levels up to 50 μM in HepG2.2.15.7 cells, which are stably transfected with a complete HBV genome without HBV
infection. These results indicated that
fasiglifam only affect on HBV
infection via NTCP inhibition. For HBV treatment of
fasiglifam, further investigation including additional non clinical research in addition to the evaluation of safety and efficacy in humans would be needed in the future study.