Designed Beta-Turn Mimic Based on the Allylic-Strain Concept: Evaluation of Structural and Biological Features by Incorporation into a Cyclic RGD Peptide (Cyclo(-L-arginylglycyl-L-alpha-aspartyl-))

摘要

The (3R,5S,6E, 8S,10R)-11-amino-3,5,8,10-tetramethylundec-6-enoioc acid (ATUA; 1), which was designed as a betaII'-turn mimic according to the concepts of allylic strain and 2,4-dimethylpentane units, was incorporated into a cyclic RGD peptide. The three-dimensional structure of cyclo(-RGD-ATUA-) (= cyclo-(-Arg-Gly-Asp-ATUA-)) 4 in H_2O was determined by NMR techniques, distance geometry calculations and molecular-dynamics simulations. The RGD sequence of 4 shows high conformational flexibility but some preference for an extended conformation. The structural features of the RGD seuqence of 4 were compared with the RGD moiety of cyclo(-RGDfV-) (= cyclo(-Arg-Gly-Asp-D-Phe-Val-)). In contrast to cyclo(-RGDfV-), RGD moiety of cyclo(-RGDfV-) (=cyclo(-Arg-Gly-Asp-D-Phe-Val-)). In contrast to cyclo(-RGDfV-), which is a highly active alphavbeta3 antagonist and selecive against alphaIIbbeta3, cyclo(-RGD-ATUA-) shows a lower activity and selectivity. The structure of the ATUA residue in the cyclic peptide resembles a betaII'-turn-like conformation. Its middle part, adjacent to the C=C bond, strongly prefers the designed and desired structure.