Piptides: A New Peptidomimetic Design For Biomolecular Interactions

Small molecule probe development is pivotal in biomolecular science. Peptidomimetics are generally interesting if they resemble peptides or protein-fragments and display biological activities. To achieve this, it is desirable that they have parameters such as conformational rigidity (relative to analogs peptides of a similar length), proteolytic stability, and the ability to display natural pharmacophores, i.e. amino acid side-chains. They must also be easily prepared on a solid phase. This dissertation presents a new peptidomimetic design that we call piptides. Advantages of the design include efficient and accessible synthesis of oligomers featuring most natural amino acid side-chains, atom spacings that correspond to peptide main-chains, and enhanced rigidity relative to α-peptides, β-peptides and peptoids. Solution-phase syntheses of the monomers and solid-phase routes to piptides were developed. Its physiochemical properties, which includes predicted physiological parameters, pH and proteolytic stabilities, CD, and NMR were also elucidated. Illustrative application of piptides against protein-protein interaction (PPI) targets, specifically EGF•EGFR and uPA•uPAR, were explored. The Exploring Key Orientations, EKO, strategy was used to evaluate piptide candidates for this. Compounds were found to have low micromolar values for IC50 and Kd for both studied PPI targets