Our lab is actively engaged in the synthesis of peptide mimics, natural products, and their congeners. These compounds are used to probe molecular recognition events and to target disease-relevant pathways. We are particularly fascinated by the impact of structurally complex amino acids on conformation and bioactivity.
Peptide Mimicry & Folding
Protein secondary structures mediate a variety of biological processes and provide design cues for the development of new therapeutics. Unfortunately, removal of ordered peptide domains from the context of larger proteins compromises folding and stability. Our lab is pursuing N-heteroatom-substituted peptide foldamers and constrained peptide mimics capable of modulating protein-protein interactions. We are especially interested in developing efficient synthetic routes toward beta-sheet mimics, and in parsing the impact of discrete chemical modifications on conformation.
Natural Product Synthesis and SAR
Nature remains a prolific source of biologically active drug candidates, with almost half of all FDA-approved therapeutics classified as natural product derived or inspired. We are pursuing the synthesis of non-ribosomal peptides and other natural products in which complex amino acids are important for biological activity. Total synthesis of these molecules provides a platform for the development of new tactics/methodologies, and allows us to investigate the utility of new amino acid motifs in the context of peptidomimetic drug design.
We have a number of active collaborations to target clinically validated biological pathways. Current efforts are aimed at modulating beta-sheet protein-protein interactions important in oncogenesis and neurodegeneration, as well as small molecule antagonists of ER stress response pathways in cancer.
We thank the following organizations for support of our research: