SYNTHESIS AND CONFORMATIONAL-ANALYSIS OF LINEAR AND CYCLIC-PEPTIDES CONTAINING SUGAR AMINO-ACIDS

Sugar amino acids (SAAs) were designed and synthesized as new non-pept ide peptidomimetics utilizing carbohydrates as peptide building blocks . They represent sugar-like ring structures that carry an amino and a carboxylic functional group and have a specific conformational influen ce on the backbone of peptides due to their distinct substitution patt erns in rigid pyranose sugar rings. Five different SAAs (SAA1 alpha, S AA1 beta, SAA2, SAA3, and SAA4) have been synthesized that show the ab ility to constrain linear backbone conformations or distinct turn stru ctures. Linear and cyclic peptides involving SAAs have been prepared i n solution as well as by sold phase synthesis. SAA1 alpha and SAA2 wer e incorporated into two linear Leu-enkephalin analogs, replacing the n atural Gly-Gly dipeptide. NMR studies provide evidence for the conform ation-inducing effect of the carbohydrate moiety. SAA2, and SAA3 have been placed in cyclic hexapeptide analogs of somatostatin; SAA4 was in corporated in a model peptide, The conformation of the cyclic peptides cyclo(-SAA2-Phe-D-Trp-Lys-Thr-), cyclo(-SAA3-Phe-D-Trp-Lys(Boc)-Thr(t Bu)-), and cyclo(-SAA4-Ala-D-Pro-Ala-Ala-) have been analyzed by vario us NMR techniques in combination with distance geometry calculations a nd subsequent molecular dynamic simulations. The determined solution c onformations were compared to representative idealized peptide backbon es. SAA2 and SAA3 induce a beta-turn structure while SAA4 mimics a gam ma-turn. Both enkephalin analogs were not active in the guinea pig ile um assay. The somatostatin analog containing SAA2 has an inhibition co nstant (IC50) of 0.15 mu M for the inhibition of the release of growth hormone.