Solid-Phase Synthesis of the Lipopeptide Myr-HBVpreS2-78, a Hepatitis B Virus Entry Inhibitor 英文参考文献.docVIP

Molecules 2010, 15, 4773-4783; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Solid-Phase Synthesis of the Lipopeptide Myr-HBVpreS/2-78, a Hepatitis B Virus Entry Inhibitor Alexa Schieck 1, Thomas Müller 1, Andreas Schulze 2, Uwe Haberkorn 1, Stephan Urban 2 and Walter Mier 1,* 1 Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany 2 Department of Infectious Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany * Author to whom correspondence should be addressed; E-Mail: walter.mier@med.uni-heidelberg.de; Tel.: +49-6221-56 7720; Fax: +49-6221-56 33629. Received: 20 May 2010; in revised form: 2 July 2010 / Accepted: 5 July 2010 / Published: 7 July 2010 Abstract: Chronic HBV infection is the leading cause of liver cirrhosis and hepatocellular carcinoma (HCC). Synthetic peptides derived from the N-terminus of the large HBV envelope protein (L-protein) have been shown to efficiently block HBV entry. Myr- HBVpreS/2-78, the parent compound of these drugs, inhibits human HBV infection in vitro and in vivo. An efficient synthesis is required, as these peptides constitute a novel class of anti HBV drugs. Consequently, the solid phase synthesis of the N-terminal 77 amino acids of the viral L-protein was studied in detail. The peptide was N-terminally myristoylated to resemble the natural, postranslationally modified protein. The synthesis was monitored using the Fmoc cleavage pattern of the solid phase synthesis on a standard peptide synthesizer and by LC-MS analyses of the arising side products. “Difficult sequences” in the positions 42-47 of the peptide sequence complicate the efficient synthesis of the 77-mer peptide HBVpreS/2-78. Attempts were undertaken to optimize the synthesis by heating, double coupling or the use