Carbohydrates as Templates for de novo Design of Proteins

  • Jensen, Knud Jørgen (Project Manager)
  • Brask, Jesper (Project Participant)

    Project Details


    Proteins owe their properties to the precisely folded three-dimensional structures of their polypeptide chains. Many proteins can spontaneously refold in vitro after having been completely unfolded; how this occurs has come to be known as the "protein folding problem". A common motif in proteins is the 4-alfa-helix bundle consisting of four amphiphilic peptide strands forming a hydrophobic core. To simplify the protein-folding problem of linear polypeptides it has been suggested to assemble by chemical means peptides, which have an amphiphilic secondary structure on a topological carrier molecule (a scaffold or template) to mimic, for example, a 4-alfa-helix bundle. The template reinforces and directs the folding process, thus determining the folding process.
    Carbohydrates are polyfunctional molecules composed of relatively rigid monomers. Regiospecific attachment of peptide chains to carbohydrate templates gives control of the distance-geometry of the relative placement of peptide strands in protein models. For brevity and clarity, we propose the terms carbopeptides and carboproteins for peptides and protein models assembled on a carbohydrate template.
    Our general strategies for the use of monosaccharides in the solid-phase synthesis of protein models involves four steps: (1) the per-O-acylation of a monosaccharide (D-Gal) with the spacer amino acid (beta-Ala); (2) attachment of a bifunctional linker to the anomeric center of the per-O-acylated monosaccharide; (3) attachment of the template linker to a solid support; (4) solid-phase peptide synthesis on the template. In a preliminary report we have described the the assembly of an amphiphilic peptide sequence, Ac-Glu-Ala-Leu-Glu-Lys-Ala-Leu-Lys-Glu-Ala-Leu-Ala-Leu-Ala-Lys-Leu-Gly, on a D-Gal template.
    Effective start/end date01/02/199731/12/2001


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