SYNTHESIS AND SOLUTION STRUCTURE OF AN S-GLYCOSYLATED CYCLIC HEXAPEPTIDE - EVIDENCE FOR CONFORMATIONAL CHANGE INDUCED BY GLYCOSYLATION

Synthesis and conformational analysis of the S-glycosylated cyclic hex apeptide cycio(-D-Pro(1)-Phe(2)-Cys(3)(tetra-O-acetyl- beta-D-galactop yranosyl)-Trp(4)-Lys(Z)(5)-Phe(6)-) I was carried out to examine the i nfluence of a saccharide residue in position i of a standard beta-turn on the formation of reverse turns and on the biological activity. Syn thesis was carried out in the liquid phase employing a galactosylated cysteine building block. The cyclization reagents DPPA/NaHCO3 avoided high dilution conditions. Spectroscopic data were extracted from home- and heteronuclear 2D-NMR techniques (TOCSY, NOESY, HMQC, HMQC-TOCSY, HMBCS-270). For structural refinement restrained molecular dynamics (M D) simulations in vacuo and with explicit DMSO as solvent were perform ed. Finally, simulations in DMSO without experimental restraints provi ded insight in stability and dynamics of the structural model. A compa rison of the S-glycosylated Cys(3) peptide with the analogous Thr(3) p eptide exhibits a similar overall conformation of the hexapeptide [bet a II' D-Pro-Phe and another beta-turn about Trp(4)-Lys(5)(Z)](Z)I, How ever, the latter shows a distinct dynamic flip beta I, beta II in the glycopeptide, whereas the Thr-analogue only populates beta I. This inf luence is attributed to a beta I stabilizing effect of a hydrogen brid ge of Thr-O-7 in position i to the NH of the amino acid in position i + 2, which is lacking in the glycosy]ated compound. (C) Munksgaard 199 4.