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Binding assays and digestion assays are in progress to determine how we can improvePK15 sequence to obtain a structure resistant to trypsin. The best compound could be agood candidate for further development of therapeutic agents.References1. Meloen, R., Timmerman, P., Langedijk, H. Molecular Diversity 8, 57-59 (2004).2. Timmerman, P., Puijk, W.C., Meloen, R.H. J. Mol. Recogn. 20, 283-299 (2007).3. Heinis, C., Rutherford, T., Freund, S., Winter, G. Nature Chem. Biol. 5, 502-507 (2009).4. Izdebski, J., Witkowska, E., Kunce, D., Orlowska, A., Baranowska, B., Radzikowska, M., Smoluch,M. J. Pept. Sci. 8, 289-296 (2002).5. Haviv, F., et al. J. Med. Chem. 36, 363-369 (1993).6. Coy, D., Hocart, S.J., Sasaki, Y. Tetrahedron 44, 835-841 (1988).7. Douat, C., Heitz, A., Martinez, J., Fehrentz, J.-A. Tetrahedron Lett. 41, 37-40 (2000).255
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Structure-Activity Relationship Study of an Interleukin-1Receptor Negative Modulator by α-Amino γ-Lactam ScanningLuisa Ronga 1 , Kim Beauregard 1 , Andrew G. Jamieson 1 ,Daniel St-Cyr 1 , Christiane Quiniou 2 , Sylvain Chemtob 2 ,and William D. Lubell 11 Départment de Chimie, Universitè de Montréal, Montreal (Quebec), H3C 3J7, Canada;2 St.-Justine Hospital Research Centre, Université de Montréal, Montreal (Quebec),H3T 1C5, CanadaIntroductionAgl (α-amino γ-lactam) residues in peptides have stabilized β-turn structures and enhancedpotency and receptor selectivity [1], underlining their importance as synthetic tools inconformational analysis and drug discovery. The single and multiple insertion of Agl into apeptide sequence has been performed on solid support using a six-member cyclicsulfamidate derived from homoserine to install the amino lactam residue onto the peptidechain [2,3]. Moreover, the introduction into a peptide sequence of a beta-hydroxy-gammalactam(Hgl, a constrained Ser/Thr mimic) was recently achieved by employingN-(Fmoc)oxiranylglycine as a bis-electrophile in TFE to sequentially alkylate and acylatethe growing peptide on solid support [4]. These methods have provided access to severalanalogs of the allosteric negative modulator of the interleukin-1 receptor 101.10 (D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala: rytvela) [5]. With the goal to better understand theconformational preferences responsible for the biological activity of 101.10, a library of(R)- and (S)-Agl analogs of rytvela was produced, including analogs possessing two Aglresidues. Analogs of rytvela were also synthesized by replacing the D-Thr residue with Hglresidues of different stereochemistry. The efficacy of these lactam analogs was ascertainedby measuring their influence on IL-1-induced human thymocyte TF-1 proliferation. Certainanalogs retained activity and some exhibited improved properties relative to those of theparent peptide. Moreover, the conformational preferences of the Agl analogs of rytvelawere examined by circular dichroism (CD) spectroscopy. Compared to the parent peptide,which is characterized by a disordered structure, the lactam analogs often exhibited spectraindicative of turn-like conformation.Results and DiscussionThe assessment of efficacy in inhibiting IL-1 induced TF-1 cell proliferation demonstratedthat replacement of the N-terminal D-Arg 1 residue by (R)-Agl, in rytvela analog (R)-Agl1,led to a 2.2 fold increase in efficacy (44%) compared to the parent peptide. Moreover,replacement of D-Val 4 by (R)-Agl gave the rytvela analog (R)-Agl4, which exhibitedsimilar activity (78%) as the parent peptide.In light of the improved activity of (R)-Agl1 and the maintained potency of (R)-Agl4,the combination of two (R)-Agl residues at positions 1 and 4 in rytvela was explored. In theassay for IL-1-induced proliferation of human thymocytes, (R)-Agl1-(R)-Agl4 maintained asimilar inhibitory effect (79%) as the parent peptide. At first assessment, the results suggestthat the side chains of both D-Arg1 and D-Val4 may not be necessary for activity.The CD spectrum of rytvela in water was compared to those of the Agl analogs.Enantiomeric D-peptides, such as rytvela and its lactam analogs, exhibit inverted curveshapes indicative of mirror image secondary structures to those formed by L-peptides [6].256
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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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Proceedings of the 31 st European P
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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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