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processes are blocked. Interestingly, using HPLC and NMR, we were also able to unravelan intermediate state in the interconversion process, namely the racemate of the trans/cisand cis/trans configurational isomers. This phenomenon was further, albeit indirectly,demonstrated by photoisomerization of the chiral dipeptide based on one azobenzeneresiduewith H-L-Leu-OMe, which afforded two diastereomeric intermediates, as detectedby HPLC and verified by NMR. We are currently extending this study to more complexmolecular systems, where the two amino acids, appropriately N α -functionalized, are boundto various type of nanoparticles.References1. Pieroni, D., Fissi, A., Angelini, N., Lenci, F. Acc. Chem. Res. 34, 9-17 (2001).2. Denschlag, R., Schreier, W.J., Rieff, B., Schrader, T.E., Koller, F.O., Moroder, L., Zinth, W.,Tavan, P. Phys. Chem. Chem. Phys. 12, 6204-6218 (2010).3. Backus, E.H.G., Bloem, R., Donaldson, P.M., Ihalainen, J.A., Pfister, R., Paoli, B., Caflisch, A.,Hamm, P. J. Phys. Chem. B 2010, 114, 3735-3740 (2010).4. Irie, M. Bull. Chem. Soc. Jpn. 81, 917-926 (2008).13
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Stabilization of β Turn Conformation in Melanocortin-LikePeptide by Click Side Chain-To-Side Chain CyclizationChiara Testa 1,2,3 , Stefano Carganico 1,2,3 , Francesca Nuti 2,3 ,Mario Scrima 4 , Anna Maria D’Ursi 4 , Marvin L. Dirain 5 ,Nadeje Lubin Germain 1 , Carrie Haskell-Luevano 5 , Michael Chorev 6,7 ,Paolo Rovero 2,8 , and Anna Maria Papini 1,2,31 Laboratoire SOSCO – EA4505 Université de Cergy-Pontoise Neuville-sur-Oise, 95031,Cergy-Pontoise, France; 2 Laboratory of Peptide & Protein Chemistry & Biology, PoloScientifico e Tecnologico, University of Florence, I-50019, Sesto Fiorentino (FI), Italy;3 Department of Chemistry “Ugo Schiff”, University of Florence, I-50019, Sesto Fiorentino(Fi), Italy; 4 Department of Pharmaceutical Science, Via Ponte Don Melillo 11C, Salerno,I-84084, Italy; 5 Department of Pharmacodynamics, University of Florida, Gainesville,FL, 32610, U.S.A.; 6 Laboratory for Translational Research, Harvard Medical School,One Kendal Square, Building 600, Cambridge, MA, 02139, U.S.A.; 7 Department ofMedicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, U.S.A.;8 Department of Pharmaceutical Science, Polo Scientifico e Tecnologico,University of Florence, Via Ugo Schiff 3, I-50019, Sesto Fiorentino (Fi), ItalyIntroductionInteraction of linear and flexible peptides with their macromolecular target, such asGPCRs, involves a limited number of closely related conformations that are recognized by,bind to and either activate or block the biological activity of these targets. Hence, the socalled bioactive conformation represents only a small subset of the larger ensemble ofaccessible conformations which are in a dynamic equilibrium. A growing arsenal ofstructural rigidifications offers means to capture and stabilize the biological conformationof linear peptides in an effort to enhance target specificity, biological potency, bindingaffinity and metabolic stability [1,2]. Herein we report on the extension of an innovativestrategy for stabilization peptide β-turn conformation by side chain-to-side chaincyclization employing a bridge containing a [1,2,3]triazole [5-8].Results and DiscussionMelanocortin GPCR receptors (MCRs) are involved in many biological pathways,including sexual function, feeding behaviour, energy homeostasis and pigmentation,making them potential targets for drugs to treat diseases such as obesity and sexualdysfunction. Therefore, understanding the bioactive conformation of the ligand and thestructure of the receptor–ligand complex is crucial to design more potent and MCR-subtypeselective ligands. MT-II is a potent long acting non-selective super-agonist of MCRs,characterized by lactam bridge between residues Asp 5 and Lys 10 stabilizing a type-II β turnstructure that is critical for its bioactivity [3]. The minimal active sequence is identified bythe tetrapeptide His 6 -D-Phe 7 -Arg 8 -Trp 9 [4], which is included in the cyclic portion formedby lactam ring. In previous work [5] we designed and studied a new intramolecular sidechain-to-side chain [1,2,3]triazolyl-bridged modification. This 1,4-disubstituted[1,2,3]triazolyl moiety is bioisosteric to the peptide bond and was recently introduced by usas an α-helix stabilizing rigidification replacing the i-to-i+4 side chain-to-side chainbridging lactam in peptides derived from parathyroid hormone-related protein (PTHrP). Inthe current study, we applied the [1,2,3]triazolyl-bridging strategy to stabilize a β-turnconformation in MT-II by replacing the lactam bridgewith a i-to-i+5 side chain-to-side chain cyclization viaCu I -catalyzed azido-to-alkyne 1,3-dipolar cycloaddition(CuAAC) generating 1,4-disubstituted[1,2,3]triazolyl-containing ring structures. In thisFig. 1. Azido and Alkynyl Aminoacid building blocks for FmoctBuSPPS.context, we have developed synthesis of N α -Fmoc-ωazido-α-amino-and N α -Fmoc-ω-ynoic-α-amino acids(Figure 1) by diazo-transfer of the N α -protected ω-amino-α-amino acids [6,7] and by alkylation of aNi(II) complex of the Schiff base derived from glycine14
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Peptides 2010Tales of PeptidesProce
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Peptides 2010Tales of PeptidesProce
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IntroductionWe had the distinct hon
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Subject index(S)-2-(1-adamantyl)gly
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chip 18chiral triazine condensing r
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heat stress 348helical conformation
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O-acyl isopeptide method 112obesity
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SH2-ligands 210short collagen-relat
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Author indexAboye, Teshome Leta 142
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Chi, Hongfang 480Chiche, Laurent 6C
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Geronikaki, Athina 444Gessmann, Ren
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Kostova, Kalina 528Kotzia, Georgia
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Nagata, Koji 162Nagayev, Igor Yu. 5
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Salvarese, Nicola 518Sammet, Benedi
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Vauquelin, Georges 138Veiga, Ana Sa
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