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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, 2010Exploring the HBV Envelope Protein forLiver-Specific Drug TargetingThomas Müller 1 , Alexa Schieck 1 , Barbro Beijer 1 , Anja Meier 2 ,Uwe Haberkorn 1 , Stephan Urban 2 , and Walter Mier 11 Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld400, 69120, Heidelberg, Germany; 2 Department of Molecular Virology, UniversityHospital Heidelberg, Im Neuenheimer Feld 350, 69120, Heidelberg, GermanyIntroductionMany pharmaceuticals used today do not exhibit a specific targeting to their site of action.We are currently developing a novel drug, named Myrcludex B, against hepatitis B virusinfections [1]. It is derived from the 47 N-terminal amino acids of the large hepatitis Benvelope protein and is myristoylated at the N-terminal (Myristoyl-HBVpreS/2-48). Thepeptide accumulates exclusively inside the liver; already 10 minutes after intravenousinjection, 88% of the injected peptide was found inside the liver (Figure 1). In in vitroFACS experiments it was shown that the peptide binds specifically to various liver celllines including primary human hepatocytes. Encouraged by these findings, the peptide isnow further investigated as a possible drug carrier for targeting different drugs to the liver.In order to demonstrate the versatility of this carrier concept, different compounds wereselected. Penicillin was chosen as a representative of antibiotics. The antimalarialprimaquine was selected, because it is known to eradicate persisting forms of the parasiteinside the liver. Doxorubicin is a standard chemotherapeutic against hepatocellularcarcinoma but leads to severe side effects. The advantage of drug targeting is the loweramount of drug required for therapy accompanied by a reduction of side effects.Results and DiscussionBiodistribution studies revealed that all the synthesized drug conjugates predominantlytarget the liver. However, the pharmacokinetic behavior is altered depending on theconjugated drug. Especially in the case of the doxorubicin derivative, the excretion wasmuch faster compared to the peptide itself. Although the initial liver uptake 10 minutes postinjection was comparable (93% versus 88% for Myristoyl-HBVpreS/2-48), 1 hour postinjection the amount inside the liver had already decreased significantly to 51% versus 81%(Figure 2). However, in the case of the penicillin derivative, the excretion kinetics arecomparable to Myristoyl-HBVpreS/2-48 but the absolute values are significantly lower.% ID / Organ10090807060504030201010 min0Blood Heart Lung Spleen Liver Kidney Muscle Brain Intestine Duodenum TailFig. 1. Biodistribution of radioactively labeled Myristoyl-HBVpreS/2-48 in female NMRImice.1 h4 h24 h28