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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, 2010Synthesis of Glycopeptides Potential Inhibitors of HumanRhinovirus 3C ProteaseDantcho L. Danalev 1,2 , Nadège Lubin-Germain 2 , Jacques Uziel 2 ,and Jacques Augé 21 University of Chemical Technology and Metallurgy, Department of Organic Chemistry,Sofia, Bulgaria, dancho_danalev@yahoo.com; 2 Université de Cergy-Pontoise,Cergy-Pontoise, France, Nadege.lubin-Germain@u-cergy.frIntroductionRecently, due to rapidly and dramatically changing climatic conditions, our environment isalso varying quickly. Simultaneously, we are witnessing the emergence of several new andmore resistant viruses such as HIV virus, AH1N1 influenza virus and an ever increasingresistance of viruses to applied drugs. In this global context, synthesis of completely new ormodified antiviral agents and vaccines is of a great interest for medical practice.Human rhinovirus (HRV) is a small picornavirus responsible for the common cold.Some enzymatic and structural proteins required for viral replication are generated by theviral encoded 3C Protease (3CP). The HRV 3CP is specific cysteine protease able to cleaveP1-P1’ Gln-Gly amide bond. Structurally, it closely resembles trypsin-like serine protease[1]. A tripeptide aldehyde Z-Leu-Phe-Gln-H is a well know inhibitor of human rhinovirus3CP [2]. Several literature data reveal that P3 Leu residue is not important for antiviralactivity and many groups could be tolerated at this place [3].A lot of experiments connected with compounds possessing inhibitory activity againstthe cysteine-containing human rhinovirus 3C protease (3CP) revealed that some simplechanges in the 3CP substrate H-His-Leu-Phe-Gln-Gly-Pro-OH could transform it into lowmolecular strong inhibitor Z-Leu-Phe-Gln-Michael acceptor [4].A series of similar inhibitors have been synthesized and described in the literature inorder to reveal the role of different parts of the molecule on the antiviral activity [4-7]. Itwas proven that Leu residue at P3 position is not necessary for the substrate-enzymeinteraction [3]. Therefore, a wide variety of substitutes are tolerated at this position. Furtherstudies showed that aldehyde group as a Michael acceptor is not acceptable because of theirtoxicity, lack of selectivity and stability [8].Results and DiscussionHerein, we report a series of mimetics of this tripeptide by replacement of P3 Leu residuewith Ser or Lys in order to make possible further glycopeptides synthesis. A linker ofadipic acid was also incorporated between peptide and carbohydrate moieties (Figure 1).OOOXHN CH CCH 2HN CH CCH 2HN CH CCH 2RX=benzyloxycarbonyl group or WY=(CH 2 ) 3 -NH-CO-(CH 2 ) 4 -COOHor O-CO-(CH 2 ) 4 -COOHYCH 2W=H or different Mihael acceptorsCNHOR=H or OHFig. 1. General structure of aimed peptide mimetics.WDespite the large progress in peptide chemistry due to solid phase peptide synthesis (SPPS)discovered by Merrifield (1963), the synthesis of each new peptide sequence represents amajor challenge and is often unpredictable, especially when obtaining peptides with highmolecular weight and difficult sequences. The creation of new synthetic schemes forsynthesis of peptides is facilitated both by the discovery of new methods for condensationand new protective groups (alone or in combination with already known ones) as well as90