Peptide stapling is the process of linking two sites of a peptide together in the effort to create and maintain its three-dimensional shape. The function of peptides and proteins relies solely on the integrity of the three-dimensional shape; therefore, increasing the durability of the shape of a peptide or protein directly increases it’s effectiveness in a biological setting. Stapling a peptide will increase its resistance to environmental perturbations, including changes in temperature, pH, and solvent composition. Current strategies to staple peptides require the use of expensive artificial amino acids or extreme reaction conditions. We take a different approach by focusing on mild conditions and a natural amino acid, tryptophan. We have developed a Lewis base-Brønsted acid catalyzed sulfenylation of tryptophan in the practice of stapling peptides. We synthesized sulfur containing polyethylene glycol derivatives, which we have successfully used as a link between tryptophans on a peptide. Successful peptide stapling is analyzed by reverse phase chromatography, Matrix Assisted Laser Desorption Ionization (MALDI) and circular dichroism. We have been working with therapeutically relevant peptides, and our strategy shows promise that it can be applied to many different peptides.

Peptide stapling by Lewis base-Brønsted acid catalyzed sulfenylation of tryptophan

2019 Fall National Meeting

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