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peptides (2,7,9) were unable to reduce the NGF-triggered cell aggregation throughdephosphorylation of functional proteins and of adhesion molecules. We believe that thisunexpected finding results from interaction with other functional proteins than SHP-1.Their activation can occur because the 120 (115) sequence-types of SH2-domains in thehuman genome are distributed in over more than 1000 functional proteins. Thus, each typeof SH2-ligands can statistically activate about 10 different proteins. This fact and the foundpromiscuity of SH2-domains require developing of bi- or multivalent ligands [6] for signaltransduction therapy and methods for local administration.Table 1. Stimulation of recombinant human SHP-1 by linear and cyclic octapeptidesStructure Activity RingsizeBasal activity of the SHP-1 281 H-Gly-Glu-Leu-Asn-pTyr-Nle-Asp-Leu-NH 2 260 02 H-Gly-Glu-Leu-Abu-pTyr-Nle-Asp-Leu-NH 2 210 03 H-Glu-Gly-Leu-Abu-Tyr-Nle-Asp-Leu-NH 2 125 04 H-Glu-Gly-Leu-Asnψ[CO-N]pTyr-Nle-Asp-Leu-NH 2(CH 2 ) 3 -NH Gly5 H-Glu-Gly-Leu-Abuψ [CO-N]pTyr-Nle-Asp-Leu-NH 2(CH 2 ) 3 -NH Gly6 H-Glu-Gly-Leu-Abuψ [CO-N]pTyr-Nle-Asp-Leu-NH 2(CH 2 ) 4 -NH Gly7 H-Glu-Gly-Leu-Abuψ [CO-N]pTyr-Nle-Asp-Leu-NH 2(CH 2 ) 5 -NH Gly140 1745 17105 18160 1989H-Glu-Gly-Leu-AbuΨ[CO-N]pTyr-Nle-Asp-Leu-NH 2GlyCH 2 -C 6 H 10 -CH 2 -NHH-Glu-Gly-Glu-Abuψ [CH 2 -NH]pTyr-Nle-Lys-Leu- NH 2390 20420 21Activity: nmolPi/min, released from p-nitrophenylphosphateAcknowledgementsFinancial support by the Deutsche Forschungsgemeinschaft (Re 853/10-1) is gratefully acknowledged.We thank Dr. Andrea Perner for performing ESI-MS analyses, Dr. Wolfgang Guenther formeasurement of 1 H- and 13 C-NMR spectra and Manuela Flad for estimation of SHP-1 stimulation.Stabile transformed NIH3T3-cells are a generous gift from Prof. F. Boehmer.References1. Keilhack, H., Müller, M., Böhmer, S.-A., Frank, C., Weidner, K.M., Birchmeier, W., Ligensa, T.,Berndt, A., Kosmehl, H., Günther B., Müller, T., Birchmeier, C., Böhmer, F.D. J. Cell Biol. 152,325-334 (2001).2. Yang, J., Liang, X., Niu, T., Meng, W., Zhao, Z., Zhou, G.W. J. Biol. Chem. 273, 28199-28207(1998).3. Imhof, D., Wieligmann, K., Hampel, K., Nothmann, D., Zoda, M.S., Schmidt-Arras, D., Böhmer,F., Reissmann, S. J. Med. Chem. 48, 1528-1539 (2005).4. Wieligmann, K., Castro, L.F., Zacharias, M. In Silico Biology 2, 305-311 (2002).5. Zoda, M.S., Zacharias, M., Reissmann, S. J. Peptide Sci. 16, 403-413 (2010).6. Teichmann, K., Kühl, T., König, I., Wieligmann, K., Zacharias, M., Imhof, D. Biopolymers 93,102-112 (2010).211
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis of Neuropeptide Y Analogues as PET Imaging AgentsSimon J. Mountford 1 , Lei Zhang 2 , Herbert Herzog 2 , Bim Graham 1 ,and Philip E. Thompson 11 Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,Parkville, VIC, 3052, Australia; 2 Neuroscience Research Program, Garvan Institute ofMedical Research, St Vincent's Hospital, Darlinghurst, NSW, 2010IntroductionNeuropeptide Y is a 36-amino acid peptide that belongs to a family of structurally relatedpeptides including pancreatic polypeptide (PP) and peptide YY (PYY). NPY is a peptideneurotransmitter mediating effects at the central nervous system [1] (e.g. stimulation offeeding behaviour and inhibition of anxiety) and the peripheral nervous system [2] (e.g.vasoconstriction, insulin release, renal secretion, gastrointestinal secretion). These centraland peripheral activities are mediated by at least six G-protein coupled receptor subtypes(Y1, Y2, Y3, Y4, Y5, and y6) [3]. Over-expression of receptor subtype Y1 occurs in humantumours such as breast cancer [4] and therefore selective Y1-receptor peptide conjugateswith the appropriate pharmacokinetic properties may be suitable for imaging and/ordelivery of radiotherapy. However, the inclusion of auxiliary imaging groups on to peptidescan dramatically change the potency and selectivity of the resultant conjugate.Incorporation of labels must not compromise the molecular recognition of the ligand by thereceptor and retain the selectivity for the Y1-receptor. We are pursuing analogues of avariety of Y1 ligands, including novel amino acids whereby the side chain is modified toallow attachment of radiolabels or other imaging agents via click chemistry. In this paperwe report on the synthetic approaches to such compounds.Results and DiscussionWe have developed syntheses of three reported Y1 ligands, [5,6] that can be adapted forinclusion of imaging agents. Included among these, are efficient synthesis of the cyclicdisulfide-bridged peptide 1, (Figure 1), and the cyclic lactam bridged dimer, GR231118, 2.Peptides were synthesized using Fmoc-based solid phase peptide synthesis on a ProteinTechnologies PS3, automated peptide synthesizer on Rink Amide resin (0.7 meq).Couplings were performed using 3-fold excess of Fmoc-protected amino acid andHCTU/DIPEA for activation. After cleavage (Reagent K, 2h) peptides were purified byRP-HPLC. Oxidation to produce 1 was performed with 25mM NH 4 HCO 3 (aq), 18h at RT.Synthesis of the dimeric peptide, 2, was achieved by treatment of the Fmoc-protected linearprecursor Ile-Glu-Pro-Dap-Tyr-Arg-Leu-Arg-Tyr-NH 2 , with PyBOP at RT followed byFmoc-deprotection with piperidine/DMF.Fig. 1. HPLC trace of disulfide bridged peptide 1, spiked with linear precursor. ESI-MSof purified product.212
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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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Scientific programIn planning the 3
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31 st EUROPEAN PEPTIDE SYMPOSIUMSep
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published by John Wiley & Sons as a
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The Josef Rudinger AwardThis award
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Young Investigators' SymposiumThe y
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xxiv
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Design of Peptidyl-Inhibitors for G
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Synthetic Antifreeze Glycopeptide A
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Synthesis and Oxidative Folding of
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Convergent Syntheses of Huprp106-12
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Bactericidal Activity of Small Beta
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Bradykinin Analogues Acylated on Th
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Antimicrobial Activity of Small 3-(
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Interaction of Curcumin with A-Synu
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Fluorescent and Luminescent Fusion
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Cellular Expression of the Human An
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2D IR Spectroscopy of Oligopeptides
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large, non-redundant subset of prot
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The aberrantly glucosylated peptide
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Table 1. Proline cis/trans ratios o
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Table 1. Yields, UV-vis absorption
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Table 1. Purity of the targeted tri
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processes are blocked. Interestingl
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(tb4 n ,1 m )MTII(tb1 n ,4 m )MTIIF
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Fig. 2. a) Part of the 400 MHz HR-M
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Once printed, the amino acid partic
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A) PSA, few seconds73B) PSA, 45 min
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short β strands. In contrast, nume
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neg. control Cs9-Rhd MM-218Fig. 2.
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Table 1. The general structure of t
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% ID in the liver 1 h p.i.100908070
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Peptidyl phosphoranes were first re
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obtained from the same sardines and
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MccJ25 variants were produced by si
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Fig. 2. Proposed signaling mechanis
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Table 1. mCD4-HS12 antiviral activi
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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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