Carbopeptides: carbohydrates as potential templates for de novo design of protein models

De novo design of proteins has evolved into a powerful approach for studyin g the factors governing protein folding and stability. Among the families o f structures frequently studied is the 'four-helix bundle' in which four al pha-helical peptide strands, linked by loops, form a hydrophobic core. Asse mbly of protein models on a template has been suggested as a way to reduce the entropy of folding. Here we describe the potential use of a carbohydrat e as such a template. The monosaccharide D-galactose was per-O-acylated wit h (N-beta-Fmoc-beta Ala)(2)O to give a penta-substituted derivative, which was converted to the corresponding glycosyl bromide and used for the glycos ylation of 4-hydroxymethylbenzoic acid pentafluorophenyl ester (HMBA-OPfp). The beta-glycosidic carbohydrate template (N-beta-Fmoc-beta Ala)(4)-beta-D -Galp-(1-O)-MBA-OPfp thus obtained was coupled to a PAL-PEG-PS resin and si multaneously extended at the four arms to yield, after cleavage from the so lid support, a carbopeptide with four identical peptide strands. Extension of this concept to, for example, synthesis of novel multiple antigenic pept ides (MAPs) and synthesis of carbohydrate clusters can be easily envisioned . The ability to efficiently synthesize such structures sets the stage for further studies to test whether the carbohydrate templates do indeed nuclea te folding.