Synthesis and in vitro Characterization of Triazole-Stapled Bim Alpha-Helical Peptides
Kinch, Logan D.
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The Bcl-2 protein family has been shown to play a vital role in the cell apoptosis process. Within this family is Bim, a pro-apoptotic protein, which forms a heterodimer with Bcl-2 allowing for the eventual release of caspases from the mitochondria leading to cell death, a necessity for normal cell functioning. Optimizing this interaction between the two proteins may allow for the development of tracers for in vitro and in vivo assays and possibly a means to combat the rapid proliferation of cells, a hallmark of cancer. The goal of the research presented in this paper is to stabilize the region of the Bim peptide, residues 85-106, which interacts with Bcl-2. Successful synthesis will induce α-helicity allowing for increased binding affinity and cell permeability as well as inhibition of proteolytic degradation. Stabilization was attempted by means of “click chemistry” and the formation of a triazole staple in an i and i+4 amino acid position. Analysis of the stapled peptides through a fluorescence polarization competitive binding assay showed minimal difference in IC50 values between linear and stapled α-helical peptides.