Institution: | a Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain b Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain c Instituto de Estructura de la Materia (CSIC), Serrano 119, 28006 Madrid, Spain d Departamento de Farmacología, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain |
Abstract: | To probe the importance of a proposed β-turn within residues S9-R12 of PACAP for recognition by VIP/PACAP receptors, compounds 1 and 2, two conformationally restricted analogues of PACAP27 incorporating respectively (S)- or (R)-IBTM as type II or II′ β-turn dipeptide mimetic at the Y10-S11 position, were synthesized. According to 1H NMR conformational analyses in aqueous solution and 30% TFE, both PACAP27 and the S-IBTM10,11]PACAP27 analogue 1 adopt similar ordered structures. PACAP27 shows an N-terminal disordered region (residues H1-F6) and an -helical conformation within segment T7–L27. For residues S9–R12, our data seem more compatible with a segment of the -helix than with the β-turn previously proposed for this fragment. In compound 1 the -helix, also spanning T7–L27 residues, appears slightly distorted at the N-terminus relative to the native peptide. Although this distortion could lead to the marked decrease in binding affinity of this compound at the VIP/PACAP receptors, the lack of the Y10 side chain in analogues 1 and 2 could also significantly affect the binding of these compounds. |