How Scientists Found the Doorway Hepatitis B Uses to Enter Liver Cells — And a Peptide to Block It

Expert review article covering the historical progression from unknown HBV entry mechanisms to NTCP receptor identification, including the development of cell culture systems, identification of viral determinants of infectivity, and clinical translation through the peptide entry inhibitor Myrcludex B.

Hepatitis B chronically infects approximately 300 million people worldwide and causes nearly 900,000 deaths per year from liver cancer and cirrhosis. Current treatments suppress but rarely cure the virus. The discovery of NTCP as the entry receptor — and the peptide drug Myrcludex B (now approved as bulevirtide/Hepcludex) that blocks it — represents one of the most successful examples of receptor discovery leading directly to a new class of peptide-based antiviral drugs. It's also the first effective treatment specifically for hepatitis D, which was previously untreatable.

The NTCP discovery and Myrcludex B development represent a textbook example of how basic science translates to clinical therapy. Understanding exactly how a virus enters cells enabled the design of a peptide that mimics the viral surface protein and competitively blocks entry. This 'entry inhibitor' strategy — already proven for HIV with enfuvirtide — now has a second major success story. For hepatitis B cure research, entry inhibitors combined with other antivirals may eventually achieve what current treatments cannot: functional cure.

As a review, this synthesizes existing knowledge rather than presenting new data. At the time of publication (2016), Myrcludex B was still in clinical trials (it has since been approved). The review predates some of the latest clinical outcome data. NTCP-based therapies block entry of new viruses but don't eliminate existing viral DNA reservoirs in liver cells.