Conformational studies of 3,4-dideoxy furanoid sugar amino acid containing analogs of the receptor binding inhibitor of vasoactive intestinal peptide

Abstract

Conformational analysis of vasoactive intestinal peptide (VIP) receptor binding inhibitor Leu 1-Met 2-Tyr 3-Pro 4-Thr 5-Tyr 6-Leu 7-Lys 8 1 by various NMR techniques and constrained molecular dynamics (MD) simulation studies revealed that the molecule had a turn structure involving its Tyr 3-Pro 4-Thr 5-Tyr 6 moiety with intramolecular hydrogen bond between Tyr 6NH→Tyr 3CO. In order to mimic the structure of 1 , peptidomimetic analogs 2– 4 were synthesized using conformationally constrained scaffolds of 3,4-dideoxy furanoid sugar amino acids (2 S,5 R)-ddSaa1 5 and its enantiomer (2 R,5 S)-ddSaa2 6 . All these analogs displayed well defined three-dimensional structures akin to that found in 1 . Peptides 2 and 3 , which differed only in the sugar amino acid stereochemistry, show propensity of structures with identical intramolecular hydrogen bonds between ThrNH→MetCO. A similar structure with a hydrogen bond between TyrNH→MetCO was observed in 4 .