Solid-Phase Synthesis and CD Spectral Analysis of IL1RAllosteric Modulator 101.10 Bearing Multiple Agl-Residues

摘要

Agl (a-amino y-lactam) residues in peptides have stabilized p-turn structures and have enhanced potency and receptor selectivity [1], underlining their importance as synthetic tools in conformational analysis and drug discovery [2]. The solid-phase synthesis of Agl peptide sequences has been performed on SynPhase lanterns [3] using a six-member cyclic sulfamidate derived from homoserine to annulate the amino lactam residue onto the peptide chain. Parallel synthesis of Agl analogs of the allosteric modulator 101.10 (D-Arg-D-Tyr-D-Thr-D-Val-D-GluD-Leu-D-Ala, rytvela) of the interleukin-1 receptor (IL-1R) [4] was performed by split and mix chemistry on the lanterns, including analogs with two Agl residues in the same peptide sequence. Conformational analysis of the Agl analogs of rytvela by CD spectroscopy is now reported and shows the pronounced influence of the lactam constraint on peptide conformation.