Conformationally restricted PACAP27 analogues incorporating type II/II ' IBTM beta-turn mimetics. Synthesis, NMR structure determination, and bindingaffinity

To probe the importance of a proposed U-turn within residues S9-R12 of PACA P for recognition by VIP/PACAP receptors, compounds 1 and 2, two conformati onally restricted analogues of PACAP27 incorporating respectively (S)- or ( R)-IBTM as type II or II' beta -turn dipeptide mimetic at the Y10-S11 posit ion, were synthesized. According to H-1 NMR conformational analyses in aque ous solution and 30% TFE, both PACAP-27 and the [S-IBTM10,11]PACAP27 analog ue I adopt similar ordered structures. PACAP27 shows Lin N-terminal disorde red region (residues H1-F6) and an alpha -helical conformation within segme nt T7-L27. For residues S9-R12, our data seem more compatible with a segmen t of the alpha -helix than with the beta -turn previously proposed for this fragment. In compound 1 the alpha -helix, also spanning T7-L27 residues, a ppears slightly distorted at the N-terminus relative to the native peptide. Although this distortion could lead to the marked decrease in binding affi nity 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 t hese compounds. (C) 2001 Elsevier Science Ltd. All rights reserved.