CAREER: Mechanistic Investigation of Covalent Protein Targeting via Genetically Encoded Reactivity

Researchers from the University of Chicago are investigating the molecular principles that govern productive covalent protein targeting. Covalent inhibitors have emerged as an important class of medicines owing to their high potency and durable target engagement. However, designing effective covalent inhibitors remains challenging because strong binding alone does not reliably predict covalent engagement. The research team will develop a genetically encoded discovery platform to identify molecules that efficiently form covalent bonds with protein targets and use these molecules to determine how molecular recognition and chemical reactivity cooperate to drive covalent engagement. Their discoveries could establish general design principles for covalent protein targeting and enable new biotechnologies for drug discovery. The project will integrate these advances into undergraduate education and provide hands-on research experiences for undergraduate and high school students. This project will leverage genetically encoded reactivity to study covalent protein targeting in a systematic manner. The discovery platform will identify a diverse array of covalent inhibitors with distinct binding and reactivity profiles, including 1) high affinity and high covalent reactivity, 2) high affinity and modest reactivity, 3) modest affinity and high reactivity, and 4) modest affinity and modest reactivity. These ligands will be characterized using complementary biochemical and biophysical approaches to determine how the high reactivity group presentation, molecular geometry, conformational rigidity, and the local protein environment influence covalent bond formation. The resulting affinity-reactivity map will define the molecular features that drive productive covalent engagement and guide the design of potent and selective covalent ligands. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.