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 occurring 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.
DNA-Encoded Cyclic Peptide Libraries
Combinatorial strategies, such as DNA-encoded libraries have seen great success in producing potent hits against a variety of drug targets. Our research focuses on the development of high-throughput reaction profiling and the physicochemical assessment of DNA-peptide conjugates. We also are developing such libraries to target protein-protein interactions related to uncontrolled cell proliferation.
Targeted Protein Degradation
As degraders (e.g. molecular glues, PROTACs) have gained considerable notoriety in the past two decades we’ve expanded our lab’s interests past macrocycles. Because degraders are typically bRo5 compounds, they too can suffer from poor passive membrane permeability and metabolic stability. Our research provides tools to assess and optimize the ADME profile of these up-and-coming compounds.