Peptides and peptidomimetics are attractive drug candidates because of their high target specificity and low toxicity profiles. Developing peptidomimetics using hydrocarbon (HC)-stapling or other stapling strategies has gained momentum because of their high stability and resistance to proteases, however, they have limitations (e.g., two-step synthesis and low yield). Our laboratory developed a stapling technique based on a synergistic relationship of a constrained backbone from α-methylation and a π-π interaction between two phenyl rings in order to promote helicity using a unique unnatural amino acid, α-methyl-L-phenylalanine (αF)1.
My research sought to expand this framework with other non-covalent interactions, including conjugated aryl systems and host-guest inclusion complexes. The stapling strategies were first trialed in a non-bioactive control peptide, and the helicity was assessed via circular dichroism spectroscopy. The strategy was then progressed to a biologically active peptide INSL5, a product of colonic L-cells involved in colon motility regulation2,3. We will also report structure-based design, docking, and computational chemistry for developing small tripeptide-based INSL5 agonists for the G-protein coupled receptor RXFP4.