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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Preclinical Pharmacokinetics of Myrcludex B, a Novel EntryInhibitor for the Treatment of HBV InfectionsA. Schieck 1 , A. Meier 2 , T. Müller 1 , U. Haberkorn 1 , S. Urban 2 ,and W. Mier 11 Department of Nuclear Medicine, University Hospital Heidelberg, Germany, 2 Departmentof Infectious Diseases, Molecular Virology, University Hospital Heidelberg, GermanyIntroductionAbout 360 million people are living with a chronic HBV infection. Currently approvedtherapies either block reverse transcription of the HBV-pregenomic RNA in infectedhepatocytes or aim at stimulating the immune system with IFN /pegIFN . Both strategiesshow limitations as they are non-curative and in the case of nucleoside analogues,drug-resistant virus strains are likely to arise during treatment. On the search for newantiviral strategies, we have recently demonstrated that HBV L-protein derivedlipopeptides block the HBV infection in vitro [1] and in vivo [2]. The inhibition of viralHBV infection by preventing virus entry into hepatocytes constitutes a new therapeuticstrategy. Myrcludex B is a first-in-class HBV entry inhibitor currently progressing toclinical application. It consists of 47 N-terminal amino acids of the viral HBV L-proteinand is myristoylated at the N-terminus. The lipopeptide specifically binds to and inactivatesan essential HBV-receptor expressed on differentiated human hepatocytes. For thedevelopment of Myrcludex B as a new drug, pharmacodynamic and pharmacokineticanalyses are indispensable. To predict the pharmacokinetic behaviour of Myrcludex B inhumans, the lipopeptide was radioactively labelled and the organ distribution wasinvestigated in different species.HBV L-protein(A)2 48 108 164187 243 264 334PreS1 PreS2 I II SIII IV389(B)2 48GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANKVGMyrcludex B9 15GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANKVGyMyrcludex B-y131 IMGQNLSTSNPLGFFPDHQLDPAFRANTANPDWDFNPNKDTWPDANKVG yGQNLSTSNPLEFFPDHQLDPAFRANTANPDWDFNPNKDTWPDANKVG y1-482-48(G12E) steaTNNDPFKRTDLAWNGFDSVAQNDLLPNPPFNNWGDGSHQPADAKPFT y2-48_scr steaFig. 1. A) Domain structure of the large HBV surface protein and the entry inhibitorMyrcludex B. The surface of the hepatitis B virion consists of three different envelopeproteins (L, M and S). The L-protein consists of three subdomains, the preS1-domain (108aa), the preS2-domain (55 aa) and the S-domain (226 aa), which contains four transmembraneregions (I-IV). The L-protein is N-terminally myristoylated at position 2 of thepeptide sequence. (B) HBVpreS-derived peptide sequences. For radioactive labeling withiodine D-tyrosine was added to the C-terminal end of the peptides. The sequence motif aa.9-15 directs the peptide to the liver and is mandatory for the inhibitory activity of the preSderivedpeptides. The point mutation of the peptide 2-48(G12E) stea is accentuated in grey.356