The proposed research focuses on biological applications of beta-amino acid oligomers (""""""""beta-peptides"""""""") that adopt specific helical conformations. Prior work in numerous laboratories, including ours, has laid a foundation of synthetic and structural beta-peptide chemistry that we will use to generate molecules with specific functions. We focus on two applications: antagonists for specific protein-protein interactions, and molecules that enter live cells. Two protein associations are targeted, Bcl-family interactions, such as Bcl-xL/Bak, and VEGF/receptor interactions; both have high biomedical significance, but they offer different interface architectures. These targets represent fundamental physicochemical challenges, since the recognition events involve large complementary molecular surfaces. High-resolution structural information on the target complexes allows us to use helical beta-peptide conformations as scaffolds to generate preliminary inhibitor designs. Diversifying the array of displayed sidechains, necessary for achieving the desired activity, is straightforward for these designs because of the oligomeric nature and predictable folding of beta-peptides. The proposed work on cell-entry molecules builds on the rapidly growing study of arginine-rich peptides and related compounds that display this activity. We have shown that guanidinium rich beta-peptides can enter live cells. The distinctive structural features of helical beta-peptides, especially their high conformational stability at short lengths, make these foldamers useful for analysis of cell entry mechanisms. The two applications we propose to study are synergistic: antagonists of intracellular protein-protein interactions such as Bcl-xL/Bak that are discovered in protein-based assays may require modification to reach their targets in cell-based assays. Achieving our functional goals will require progress in beta-amino acid synthesis, beta-peptide synthesis and beta-peptide conformational analysis, which we will pursue concurrently with the functional goals themselves. ? ?
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