Permeability Assay Development

Most membrane permeability assays are done either in cell-based systems like CACO-2 or non-membrane cell-free systems such as PAMPA. We are developing a liposome-based permeability system designed to reflect passive permeability in a physiologically accurate phospholipid bilayer.

Solid Phase Synthesis Methodology

We are developing new methods for the construction of cyclic peptides inspired by natural products such as cyclosporine A, the destruxins, and aureobasidin E. Many of these cyclic peptides contain backbone modifications such as N-methylation and lactone (depsi) linkages, which serve to increase their structural diversity and enhance membrane permeability and metabolic stability. We are interested in new synthetic methodologies that facilitate the synthesis of natural product-like libraries of cyclic peptides that contain these non-proteinogenic amino acids and linkages.

Cyclic Peptide Libraries

We are using diversity-oriented synthesis techniques to generate large libraries of cyclic peptides inspired by natural products. We are using the principles learned from the study of model systems to bias the library members toward membrane permeability and metabolic stability.

Inhibition of Protein-Protein Interactions

The structural complexity of many natural products sets them apart from common synthetic drugs, allowing them to access a biological target space that lies beyond the enzyme active sites and receptors targeted by conventional small molecule drugs. Naturally occuring cyclic peptides, in particular, exhibit a range of biological activities whose diversity is reflected in their rich structural variety. Many of these compounds penetrate cells by passive diffusion and some, like cyclosporine A, are clinically used, orally bioavailable drugs. These natural products tend to have molecular weights and polar group counts that put them outside the norm based on classic predictors of “drug-likeness”. Because of their size and complexity, cyclic peptides can show greater specificity and potency for biological targets compared to smaller acyclic compounds, and they may provide useful scaffolds for modulating more challenging biological targets such as protein-protein interactions and allosteric binding sites. Our research focuses on cyclic peptide natural products from a structural perspective, in the hope of uncovering trends that might account for their unexpected pharmacokinetic behavior.