Due to the rise of peptide pharmaceuticals, discovering methods to increase serum half-life for peptide and protein therapeutics in the human body has become increasingly important. Non-specific conjugation of polyethylene glycol (PEG) has long been used to improve protein drug effectiveness by increasing proteolytic resistance and thermodynamic stability of peptides, thus increasing serum half-life of the protein under physiological conditions. However, non-specific protein mutagenesis may alter protein function and effectiveness. To improve on this technique, our lab has done extensive research on site-specific PEGylation that both inhibits proteolysis while maintaining protein function. Our research has demonstrated that specific addition of PEG can cause stabilization effects of -1.3kcal/mol or greater. Another method of protein stabilization, peptide stapling, physically restricts protein conformation, thereby causing the protein to maintain an active form. Most methods of peptide stapling involve non-polar hydrocarbon staples. While hydrocarbon staples increase protein stability, they also contribute to solubility problems in aqueous, physiological systems. By combining site-specific PEGylation and previous stapling methods, we have created a novel PEG-stapling method. This method may increase protein stability by combining the stability due to a restricted protein conformation found in stapled peptides with the stabilizing effects due to site-specific PEGylation. In turn, this novel stapling method may lead to protein pharmaceuticals with optimized biophysical properties and longer serum half-life.<br/><br/>

PEG-Stapled peptides: A novel stabilization method

255th National Meeting (2018)

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