| The functions of biological polymers are highly dependent on their macromolecular structures, which are comprised of helices, sheets and a variety of other motifs. Advances in the field of chemical biology have given rise to the design and characterization of "foldamers", non-natural oligomers that adopt distinct secondary structures independent of external interactions. beta-peptides are a well-studied class of foldamers that possess many redeeming features as peptidomimetics, including ease of synthesis, pronounced secondary structures in water, and marked proteolytic resistance. This dissertation describes efforts to improve existing beta3-peptide inhibitors of protein-protein interactions through rational and combinatorial strategies, as well as exploration of covalent side chain bridges to influence binding affmity and cell permeability.;Chapter 1 describes strategies to optimize betaWWI-1, a previously reported 14-helical beta-peptide inhibitor of HIV fusion. One beta-peptide, bearing a m-trifluoromethylbenzene unit in place of the central indole ring, promotes cell survival in an HIV-1 infectivity assay with improvements in antiviral potency and selectivity. In Chapter 2, we attempted to further improve these beta-peptides using combinatorial chemistry. Though these particular efforts did not result in the identification of optimized inhibitors, we developed useful techniques for high-fidelity, microwave- based synthesis of large peptidomimetic libraries.;Chapter 3 describes efforts to install covalent side-chain "staples" into beta3-peptide inhibitors of p53-hDM2 complexation, generated through ring-closing metathesis of olefinic residues. Through our studies, we discovered that the location of the staple on the beta-peptide 14-helix has interesting effects on both cell permeability and hDM2 affinity.;Overall, we have made appreciable contributions to the toolbox used by chemical biologists to develop inhibitors for protein-protein interactions. Specifically, we improved the antiviral potency of a beta-peptide HIV fusion inhibitor using simple rational design and laid the groundwork for future optimization through combinatorial chemistry. We also explored the effects of stapling on beta-peptide ligands for hDM2 and observed a clear relationship between cell uptake, binding affinity, and location of the staple. Coupled with the techniques of structural biology and computational chemistry, the tools described herein can potentially be used to develop and optimize peptidomimetic inhibitors against a wide variety of biological targets. |
