Inspiration from Fluorination: Chemistry at the Biological Interface

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Overview: Using chemical and biological approaches, our research seeks to understand the details of protein-protein interactions (PPIs) with a focus on improving our knowledge of macromolecular recognition events. The impact of such findings will aid development of new medicines to significantly improve human health. Using 19F NMR, our unique contribution to this field is our ability to develop new synthetic molecules to both image and disrupt harmful PPI signaling events.

To “drug the undruggable,” we need new ways to identify protein-drug interactions and innovative chemical scaffolds that access new chemical space. Our program addresses the imperative for early-stage therapeutic development by harnessing the unique properties of fluorine incorporated at protein interfaces. PPIs offer many new opportunities for drug discovery, but selective targeting with small organic molecules remains a grand challenge in the field. Taking a new perspective, our lab is using chemical biology tools to address this medicinal chemistry challenge. Fluorine research is poised to have immediate impact due to fluorine’s roles in pharmaceutics (>20% of drugs contain fluorine), magnetic resonance imaging (19F MRI), and nuclear magnetic resonance spectroscopy (19F NMR). Capitalizing on the bioorthogonality of fluorine, we are taking a four-pronged approach to this research:

1)   Developing a protein-based 19F NMR approach for fragment-based drug design

2)  Inhibitor design for epigenetic complexes involving bromodomains as potential anticancer therapies

3) Inhibiting transcription factor-PPIs via sulfur-mediated non-covalent interactions using macrocyclic peptides

4)  Designing fluorinated imaging domains for in vivo diagnostic 19F MRI

      Given that transcription factors represent a major class of potential drug targets and the demand for structural methods to characterize them, our biomolecular 19F NMR approach for transcription factor-PPIs could significantly increase the repertoire of new targets and open up new paths forward for small molecule discovery.

In support of this approach, we develop new protein ligands through rational design of peptide macrocycles, fragment-based ligand screening, high-throughput screening, and medicinal chemistry optimization.