Novel inhibitors of NTCP-mediated viral entry

In at least 12 million (possibly up to 50 million) patients with chronic hepatitis B (CHB), secondary infection with hepatitis Delta virus (HDV) leads to an increased risk for cirrhosis, liver cancer and even fulminant liver failure. HDV is a “satellite virus” of HBV, so termed because its life cycle is dependent upon interaction of the HBV Large surface antigen protein (“L) with sodium/taurocholate cotransporting polypetide (NTCP) for viral entry into hepatocytes in a manner exactly analogous to HBV entry.

Thus, due to this structural requirement for the HBV envelope, the hepatocyte-restricted HDV life cycle requires co-infection with HBV as a “helper virus”; the HDV RNA genome replicates by hijacking cellular RNA polymerases, but the production of HDV progeny particles only occurs if the cells are also expressing the HBsAg-containing HBV envelopes. The targeting of L interaction with NTCP could potentially result in clinical benefit for both CHB and HBV/HDV coinfection.

However, the significant increase in risk for and severity of liver disease in HBV/HDV renders the medical need for HDV therapy especially urgent. HDV infection has been demonstrated to be especially amenable to treatment with the L peptide sequence-derived agent bulevirtide, which has been granted conditional approval in Europe However, its intrinsic difficulties of complex manufacturing and requirement for cold chain storage and transport have hindered FDA approval. 

In addition, the need for subcutaneous injection rather than oral dosing may hinder access and adherence in less developed parts of the world.  These downsides would likely be ameliorated by the development of a small molecule inhibitor, the development of which is currently the primary focus of our laboratory.