Preclinical studies on Myrcludex B, a novel Hepatitis B virus (HBV)-envelope protein derived entry inhibitor

The approved treatment options for chronic hepatitis B consist either of inhibition of HBV genome replication by nucleoside or non-nucleoside reverse transcriptase (RT) inhibitors or stimulation of innate or adaptive immune responses e.g. by interferon α. However, although these drugs can reduce the HBV serum titers significantly, an elimination of the virus is commonly not achieved. Furthermore, virus replication in the presence of RT inhibitors can result in the selection and amplification of resistant mutants. Inhibitors of the HBV entry could circumvent these limitations and therefore would be promising drug candidates for the therapy of HBV infection. We previously demonstrated that myristoylated HBV envelope protein-derived peptides block HBV infection in vitro (1) and in vivo (2). Based on this observation, we here describe the preclinical drug development of the lead substance called Myrcludex B. This peptide is capable to inhibit the in vitro HBV infection in a concentration dependent manner already at picomolar concentrations. Pharmacokinetic studies showed that the peptide targets the liver of even non HBV susceptible hosts with high selectivity, suggesting the presence of a species-independent but hepatocyte-specific receptor. Serum stability tests revealed a high stability of Myrcludex B with only marginal degradation of the peptide after 24h. Single dose pharmacokinetic studies in rats following intravenous or subcutaneous injections showed a selective accumulation of the peptide in the animal livers already 1h post injection. The peptide remains detectable up to 72h post administration. In single dose, 1 and 4 week toxicity studies in rats using up to 12.5mg/kg of body weight no mortality, toxicity or treatment related changes in cytokine production could be detected. Taken together these data provide compelling evidence that Myrcludex B represents a promising novel drug candidate for subsequent clinical studies applicable for HBV and HDV infections.

Literatur: (1) Gripon et al., J. Virol. 2005 79:1613-22 (2) Petersen et al., Nat Biotechnol. 2008 26:335-41

Hepatitis B virus - Myrcludex B - entry inhibitor