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% ID in the liver 1 h p.i.100908070605040302010Myristoyl-HBVpreS/2-48PenicillinDoxorubicinPrimaquine0Fig. 2. Biodistribution data of the different derivatives 1 h after intravenous application infemale NMRI mice.Furthermore, it was shown that the liver specificity arises from the particular sequence ofthe peptide. For example, in the case of the primaquine derivative, a mutant with only twoexchanges at positions 11 and 13 for the respective D-amino acid did not show the liverspecificuptake.All peptides were synthesized by employing automated Fmoc/tBu peptide synthesiswith HBTU/DIPEA activation. After the peptide synthesis and the coupling reactions,purification was carried out by RP-HPLC. All peptides and conjugates were obtained inhigh purity and the yield of the conjugation reaction was determined. For penicillin and theprimaquine derivatives, a peptide with an additional C-terminal cysteine was synthesized.Penicillin was coupled as a bromoaceto derivative [2] to the cysteine residue forming athioether bond with a yield of 45%. Primaquine was first reacted with Boc-Cys(NPyS)-OH,and secondly, the amine was deprotected with TFA. The NPyS protecting group can reactselectively with thiols forming a disulfide bond [3], in this case to the cysteine side chainwith a yield of 56%. In the case of doxorubicin, it was important to leave the amine at thesaccharide part intact [4]. The amine was Fmoc protected and then the Fmoc-protecteddoxorubicin was reacted with glutaric acid anhydride in order to yield a free carboxylicacid for coupling. This derivative was then coupled to a shortened peptide only containingone lysine residue by standard HBTU/DIPEA activation. After Fmoc deprotection, the finalconjugate was obtained with a yield of 45%. In conclusion, the peptide Myristoyl-HBVpreS/2-48 has been shown to be a versatile drug carrier and all conjugates weresynthesized in high purity and good yields.AcknowledgmentsThe authors gratefully acknowledge the Bundesministerium für Bildung und Forschung (BMFB) forfinacial support (grant 01GU0702).References1. Petersen, J., et al. Nature Biotechnology 26, 335-341 (2008).2. Li, S., Roberts, R. Chemistry and Biology 10, 233-239 (2003).3. Matsueda, R., et al. Chemistry Letters 10, 737-740 (1981).4. Nagy, A., et al. PNAS 93, 7269-7273 (1996).29