Bifunctional Helical Peptide Catalysts for Enzyme-like Reactivity and Selectivity and Selective Stapling of Natural Amino Acid Residues with Hydrophilic Squaric Acid Derivatives

• Main Author: Kinghorn, Michael James
• Format: Others
• Published: BYU ScholarsArchive 2019
• Subjects: bifunctional catalysis; peptide catalysis; enzyme-like catalysis; peptide stapling; Physical Sciences and Mathematics
• Online Access: https://scholarsarchive.byu.edu/etd/8714; https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=9714&context=etd

Peptide secondary structure provides an exceptional scaffold on which to design highly reactive and selective enzyme-like catalysts. This work describes the rational design and synthesis of a suite of helical peptide catalysts that are capable of achieving proximity-induced rate enhancement in Diels-Alder cycloadditions and indole alkylations. Microwave assisted synthesis of resin-supported polypeptides enables incorporation of non-natural amino acid residues that induce helicity (Aib) or provide functional handles on which organic catalytic residues can be attached. These small peptide catalysts exhibit binding-driven selectivity rather than relying on the inherent reactivity of substrates, which allows access to products that are not obtainable with traditional catalysts in solution. Catalyst efficiency reached up to 28,000 turn overs, which mimics natural enzymatic systems. Studies were also conducted into the stabilization of peptide secondary structure via covalent linking of nucleophilic amino acid side chains with squaric acid residues. Under mild conditions, stapling of nitrogen, sulfur and oxygen residues can readily be achieved in either organic or aqueous media. Squaric acid staples display pH selectivity for specific side chains and selective removal of diester staples (diserine staple) is demonstrated with methylamine. This new method for peptide stapling is shown to dramatically increase the proteolytic stability of eIF4E cancer inhibitor proteins, which typically are prone to quick degradation. Tyrosidine and RGD peptide analogues were synthesized and cyclized on resin in order to provide a new pathway to macrocyclization of antibacterial and integrin binding cyclic peptides.