Peptide Synthesis: A Renewable Method


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Austen Casey
Committee: Langdon Martin, Dana Emmert, Steve Cartier

Custom peptide synthesis has benefitted many areas of research including biochemistry, medicinal chemistry, and pharmaceutical science since its development in the 1950’s. Throughout its development applications have been found in selective peptide drugs, vaccines, the determination of protein function, and the study of enzyme–substrate interactions. Custom peptide synthesis may be performed in either solution- or solid-phase; recently, solid-phase peptide synthesis is preferred due to the high yields and ease of purification associated with it. The objective of this research is to develop a reusable solid-phase resin, by coupling an N-methyl cysteine derivative to TentaGel ® peptide resin. This process creates a permanent amide linkage between the resin and the cysteine derivative. After synthesis of the full-length peptide using Fmoc-based chemistry, cleavage is promoted by acidic conditions, whereby the N-methylated cysteine amide is driven to undergo an N-to-S acyl transfer, forming a thioester. Treatment of the thioester with a small-molecule thiol will trap the peptide thioester, while the N-methyl cysteine residue remains linked to the resin, and may be reused for building of subsequent peptides. As a model, an initial tripeptide—Tyr-Ala-Gly—was synthesized on the N-methyl cysteine. The model system was successfully cleaved with 40% aqueous 3-mercaptopropionic acid; the UV absorbance of tyrosine was used as an indicator of successful cleavage. A target system, containing a second peptide synthesized on the same resin, is currently under development.