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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, 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