Bicyclic Peptides as Type I/Type II beta-Turn Scaffolds

We recently reported the rational design, synthesis, and structural characterization of the most potent and selective peptide-based neurokinin A antagonist thus far described: cyclo(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 different beta-turned structures are determined by the bicyclic structure or by the amino acid type at the corner positions, we have synthesized the pseudo-symmetrical analogue cyclo(Phe(1)-Asp(2)-Trp(3)-Phe(4)-Dap(5)-Trp(6))cyclo(2 beta-5 beta). The structural characterization in the crystal state and in solution, here reported, gives an experimental evidence 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 independently from the amino acid composition.