Inhibitors of Hepatitis B Virus Attachment and Entry

Inhibition of virus entry has become a major concept in the development of new antiviral drugs. Entry inhibitors can either neutralize activities of viral surface proteins or target essential host factors such as (co)receptors. Due to its distinct tissue tropism and the highly specific viral and cellular factors involved in its entry, hepatitis B virus (HBV) is an ideal candidate for entry inhibition. Hepatitis B immunoglobulins neutralize infection by binding to the S-domain of HBV surface proteins and are used to prevent reinfection of the graft after liver transplantation. Novel S or preS-specific monoclonal antibodies are currently in development. The identification of sodium-taurocholate cotransporting polypeptide (NTCP) as a bona fide receptor has revealed a suitable target for HBV entry inhibition. NTCP receptor function is blocked by a variety of different agents including Myrcludex B, a synthetic N-acylated preS1-derived lipopeptide that inhibits HBV entry in vitro and in vivo with high efficacy. Current antiviral treatment for chronic HBV-infected patients focuses on the inhibition of the viral polymerase via nucleos(t)ide analogues (NA). Entry inhibitors in combination with NAs could block reinfection and shield naive hepatocytes that emerge from natural liver turnover, opening up new therapeutic options.