Design & Synthesis of beta-hairpin Peptidomimetics for Modulating Integrin Mediated Cell Adhesion, Abeta Fibrillogenesis and p53-MDM2 Protein-Protein Interactions

Inhibiting therapeutically important protein-protein interactions has been a tremendous challenge for medicinal chemists. The folded 3D structures of peptides and proteins, mainly comprising of secondary structural elements i.e alpha-helices and beta-sheets have created an opportunity to design small molecules and peptidomimetic inhibitors of protein-protein interaction (PPI). Hence, information about formation and stabilization of these secondary structures is very vital for designing future drugs. In this dissertation, several cyclic beta-hairpin peptidomimetics that mimic the recognition surface have been designed and synthesized as inhibitors for different targets such as integrin mediated extracellular matrix -cell adhesion in multiple myeloma, p53-MDM2 PPI, amyloid beta fibrillogenesis. Cyclization of linear peptides to restrict the number of conformations available to the linear peptide increases its affinity for the target as well as increases its proteolytic resistance. In this study, different beta turn promoters that increases the propensity of cyclic peptides to adopt beta-sheet structures have been designed and synthesized. Chapter two discusses the design and synthesis of several cyclic III (Integrin Interaction Inhibitor) peptides that block adhesion of integrins to extracellular matrix components in Multiple Myeloma tumor cells. These cyclic peptides, as assayed by TOPRO 3 assay were more potent than the parent linear with bio-activity of 1.08 microM. We have also studied structure activity relationships (SAR) of these cyclic III peptide analogs to increase the potency and bioavailability of these peptides. Chapter three describes the application of cyclic beta-hairpin peptidomimetics to inhibit abeta fibrillogenesis that is responsible for Alzheimer's disease. We have successfully designed and synthesized cyclic peptides that target hydrophobic region (17-21) of abeta fibril which is believed to cause self aggregation and plaque formation. We have also successfully explored these cyclic betahairpin peptides to disrupt p53-MDM2 interactions. Chapter five discusses the design and synthesis of novel cysteine based Peptide Nucleic Acid (PNA) monomers that are aimed to increase cellular uptake by introducing positive charge species attached to cysteine side chain. We have successfully synthesized CPNA monomers and made efforts to make PNA oligomers.