A Step Toward Achieving Peptide Based Therapeutics I. Analysis of the Effect of Olefin Position and Linker Length in Hydrocarbon Stapled Peptides II. Development and Structural Studies of Direct Peptide Inhibitors of Ras
CitationShim, So Youn. 2015. A Step Toward Achieving Peptide Based Therapeutics I. Analysis of the Effect of Olefin Position and Linker Length in Hydrocarbon Stapled Peptides II. Development and Structural Studies of Direct Peptide Inhibitors of Ras. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractTraditionally the two major classes of drugs, small molecules and biologics, have been extensively used in drug discovery. However, it is difficult to inhibit protein-protein interactions with small molecules, and targets of biologics are limited to extracellular proteins. Considering such limitations, there has been a call for a new therapeutic modality to target ‘undruggable’ proteins. Structurally-stabilized peptide therapeutics has emerged as a new class that could overcome the limitations of the previously established drug classes while retaining their benefits. Among several strategies that have been employed to constrain the conformation of peptides to enhance their pharmacological properties, the all-hydrocarbon stapling system has been particularly successful. This system combines the helix-stabilizing effects of alpha methylation with peptide macrocyclization, which confers improvement not only in helix stabilization but also in protease resistance and cell permeability. The first part of my dissertation focuses on exploring this system further by shortening the established hydrocarbon bridge length as well as moving the position of the olefin along the cross-link, and looking at the effects of these attributes on the helical propensity of the peptides by circular dichroism.
In cases where there is no structural information or obvious binding partner that has an alpha-helical component that could be used for rational design of a stapled peptide inhibitor, screening a naïve library of stabilized scaffolds using yeast cell-surface display would be an alternative starting point. Oncogenic K-Ras is one such case; the structures of Ras with its effectors have shown that they interact with Ras via beta-sheet complementation. The second part of my dissertation will describe efforts to develop peptide inhibitors that target Ras by using screening and directed evolution of libraries of an avian pancreatic polypeptide-based scaffold by yeast cell-surface display. We have identified lead peptides that disrupt the binding of effectors to Ras, and the structures of these peptides bound to Ras have been solved and analyzed, leading us to improve the lead peptides further by rational design.
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