Glycosylation is one of most important post-translational modifications of proteins, influencing protein and peptide folding, recognition, targeting and stability. While carbohydrates have been incorporated into a few bioactive peptides to change structure and function, effects of peptide glycosylation on alpha helicity have not been extensively studied. Helices are a dominant secondary structure in proteins, widely found at protein–protein interfaces and in membrane-spanning domains of proteins, with important roles in mediating protein interactions. The surfaces at most protein–protein interactions are shallow and span large areas, making them difficult to reproduce or inhibit using small hydrophobic drug-like molecules. Therefore, it is important to develop helical peptides as alternative inhibitors for protein-protein interactions. However, short synthetic peptides are not structurally well defined in water due to competition from solvating water molecules for peptide NH and CO groups and intramolecular hydrogen bonds. Some methods to stabilize helical structures in short peptides have been developed, most notably using cyclization constraints, leading to some successes in inhibiting protein–protein interactions. Nevertheless, most of the methods involve the use of hydrophobic linkers, with no example of the use of a hydrophilic group reported. Here we demonstrated that glucuronic acid can be used as a linker between amino acid side chains to make short peptides helical. Detailed circular dichroism and NMR spectral studies confirmed helix formation after the macrocyclization. Glycosylated peptides have potential for improving the properties of peptides, such as solubility, permeability, and resistance to protease cleavage, which are under investigation.

Glucuronic acid stabilizing short peptides into helix

256th National Meeting (2018)

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