BICYCLIC PEPTIDES AS TYPE-I TYPE-II BETA-TURN SCAFFOLDS

We recently reported the rational design, synthesis, and structural ch aracterization of the most potent and selective peptide-based neurokin in A antagonist thus far described: (Met(1)-Asp(2)-Trp(3)-Phe(4)-Dap(5 )-Leu(6))cyclo(2 beta-5 beta). Its bicyclic structure is characterized by a type I and a type II two beta-turn around Trp(3)-Phe(4) and Leu( 6)-Met(1), respectively. In order to understand whether the two differ ent beta-turned structures are determined by the bicyclic structure or by the amino acid type at the corner positions, we have synthesized t he pseudo-symmetrical analogue (Phe(1)-Asp(2)-Trp(3)-Phe(4)-Dap(5)-Trp (6))cyclo(2 beta-5 beta). The structural characterization in the cryst al state and in solution, here reported, gives an experimental evidenc e that the backbone of the bicyclic structure is a rigid scaffold that can be used to build both a type I and type II beta-turn independentl y from the amino acid composition. (C) 1997 John Wiley & Sons, Inc.