New Strategies for Peptide Mimicry

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ABSTRACT Our research program is focused on the development of new broadly applicable tools for peptide mimicry. Peptides are an important class of compounds that modulate a variety of biological responses, including as hormones, neurotransmitters, and antimicrobials. Occupying the space in between conventional small molecules and biologics, they can also be designed to inhibit large protein-protein interaction surfaces. However, strategies are needed to convert them into more stable molecules while retaining the bioactivity of the native peptides, ideally employing scaffolds that can adopt precise secondary structures while being amenable to rapid derivatization for library synthesis and screening. Towards that goal, we develop new methods for late-stage peptide functionalizations, and devise new strategies for the synthesis and conformational control of acyclic, highly functionalized peptidomimetics. This includes (1) the study of azapeptide folding and the development of new strategies for their chemoselective functionalization and rigidification, and (2) the discovery and application of new conformationally-constrained N-substituted glycine peptoid monomers. These novel methods are then applied to the synthesis of bioactive peptide analogs.