PACAP27 Analogues Incorporating Type II/II’ β-Turn Mimetics

Pituitary adenyl cyclase-activating peptide (PACAP) is a member of the superfamily of regulatory peptides including secretin, glucagon, VIP and GRF [1]. It exists in two bioactive forms, PACAP38 and its shortened version, PACAP27. Both exert their action through specific binding to three classes of receptors: PAC1, with higher affinity for PACAP than VIP, and VPAC1/VPAC2, which recognize PACAP38, PACAP27 and VIP with similar affinity. Although some ligands for these receptors have been described [2–4], there is still a need for specific, potent, preferably peptidomimetic agonists and antagonists of VIP/PACAP. In this regard, reliable data on the 3D conformation of PACAP are essential. Two different solution structures for PACAP27 have been proposed: i) in TFE [5], a disordered N-terminus followed by a α-helical stretch spanning residues S9–V26, with a discontinuity between K20 and K21; ii) in 25% MeOH [6], a type II ß-turn at S9–R12, and two helices spanning R12–K20 and Y22–A24. Compared to VIP, PACAP27 would have distinct conformational properties, regarding position and shape of the helix, plus the possibility of a unique ß-turn-like motif. Since minor conformational changes between VIP and PACAP may contribute to receptor selectivity, increasing the rigidity of these peptides by incorporation of well-defined secondary structure motifs is a first step in the development of selective analogues.