Séminaire CIRI : Pr. Stephan URBAN

Pr. Stephan URBAN, Dpt. of Infectious Diseases, University Hospital Heidelberg Molecular Virology & German Centre for Infectious Research (DZIF); "Discovery and development of Hepcludex/bulevirtide, the first approved drug for chronic Hepatitis D virus Infection"

Abstract:
Hepatitis B (HBV) and Hepatitis D Virus (HDV) infection requires the interaction of the shared envelope proteins with the hepatocyte specific receptor sodium taurocholate co-transporting polypeptide (NTCP). This speciesspecific interaction is mediated by an evolutionary adaptation of an essential sequence (the receptor binding domain (RBD)) within the myristoylated preS1-domain of the HBV large surface protein (L-protein) to NTCP.
Following the concept that chemically synthesized lipopeptides representing this RBD are potent inhibitors of hepadnaviral infection, both the identity of the long-sought HBV receptor was uncovered and the first approved entry inhibitor for HBV/HDV infection (bulevirtide/Hepcludex) was developed.
In this lecture I will provide a survey on the development of bulevirtide (formerly called Myrcludex B). I will highlight the initial limitations that HBV research faced at a time when only the duck hepatitis B virus (DHBV) infection system was available to study hepadnaviral entry processes. I will elaborate on the transfer of the concepts established in the DHBV model to HBV using primary human hepatocytes (PHH) and HepaRG cell lines. Although some of these concepts could not be verified in both infection systems one finally resulted in the identification of a peptidic lead substance that entered into clinical trials (bulevirtide) in 2011. I will further highlight some very surprising findings that were associated with the pharmacological behaviour of HBVpreS-1- derived peptides in vivo (e.g. liver targeting, stability) that fundamentally differed from other therapeutically applied peptides. I will finally summarize arguments that strongly support the use of an entry inhibitor to counteract HDV (and probably HBV) persistence and therefore may lead to elimination of the respective viral template (nuclear circHDV RNA and HBV cccDNA). The development of bulevirtide was an untypical enterprise, not only regarding its identification as an optimized “fragment” of an “endogenous” viral structure but also regarding its unusual properties as a stable and highly efficient peptidic drug. Its recent approval in the European Union and its successful application to HDV/HBV coinfected patients raises justified hope to become part of a curative regimen in the future.