At a fundamental level, the majority of medicines bind (or "stick") to a specific protein target. Most of these molecule-protein binding interactions are not very permanent, but the more effective drugs have extremely sticky or irreversible interactions, due to formation of a new, permanent, chemical bond with their targets. The development of new and better antibiotics and anticancer drugs is limited to molecule-protein binding interactions that form permanent bonds between new drugs and protein targets. Professor Walter Fast (University of Texas, Austin), Professor Fengtian Xue (University of Maryland), and Professor Dali Liu (Loyola University, Chicago) form a multidisciplinary team that develops new strategies to make permanent interactions by using the targeted protein to 'switch on' the bond-forming process. Their study of the underlying chemical reactions, the chemical interactions made with different types of proteins, and the three-dimensional structures of these protein-drug complexes serve as a roadmap for others working in pharmaceutical research. Dr. Fast's research team uses public outreach and focused efforts to increase recruitment of a more diverse pool of science, technology, engineering, and mathematics (STEM) students. The teams is particularly focused on recruiting students that have limited access to STEM educational opportunities. A university open house that attracts students from Kindergarten to 12th grade provides a venue where the link between basic science and pharmaceutical development is explored. Programs are also offered to provide summer research opportunities to high school students and their teachers.
With this award, the Chemistry of Life Processes Program in the Division of Chemistry at the NSF is funding Dr. Walter Fast's team to study a new strategy for making selective covalent protein modifiers. Selective covalent protein modification is a fundamental aspect of many biochemical probes and therapeutic agents, but there is a limited number of strategies used for selective modification. This research team uses organic synthesis, chemical model studies, enzymology, and X-ray crystallography to study the use of compounds that have greatly enhanced electrophilicity upon protonation, the latter being selectively induced by protein binding. This team studies the use of these 'switchable electrophiles' to target enzymes with active-site cysteine residues, non-catalytic proteins that have less-reactive cysteine residues, and more broadly, cell extracts in chemoproteomic studies. By determining the mechanisms of covalent modification and optimizing select examples as affinity probes, a roadmap is developed for the wider adoption of this strategy in covalent probe design. The research team also offers a public outreach event, high school research opportunities, and 'pipeline' school development to increase the recruitment of a more diverse pool of STEM students to universities.
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.
