Research Initiation Award: Microwave Synthesis of Imidazole Compounds to Investigate Allosteric Binding to VCP

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Research Initiation Awards provide support for junior and mid-career faculty at Historically Black Colleges and Universities who are building new research programs or redirecting and rebuilding existing research programs. It is expected that the award will (1) further the faculty member's research capability and effectiveness, (2) improve research and teaching at the home institution, and (3) engage more undergraduate students from underrepresented groups in research experiences. The project from Bowie State University, a Historically Black College/University (HBCU), seeks to study the structural requirements for allosteric binders to certain enzymatic proteins that maintain protein homeostasis in mammalian, yeast, and plant cells. The project integrates computational chemistry and biology with analogous bench research. In addition, it is designed to include undergraduate and high school students as active researchers. Collaboration and mentorship will take place throughout the project. The PI will collaborate with another researcher at Georgetown University, while the undergraduates will serve as mentors to the high school students under the supervision of the PI. VCP is an ATPase which plays a major role in the ubiquitin proteasome system (UPS). The UPS is responsible for degrading unfolded proteins through the proteasome in order to relieve cellular stress. Once tagged with ubiquitin, VCP translocates the proteins from the ER to the cytosol. VCP binders have been shown to cause an accumulation of ubiquitinated proteins which ultimately leads to cell death. This is favorable when the system is being exploited to avoid apoptosis. Six-membered ring heterocycles have been shown to act as ATP-competitive binders and are therefore unselective. Five-membered ring heterocycles bind to an allosteric site of VCP and are highly selective. However, it is unclear what the structural requirements for allosteric binders are. We propose the synthesis of imidazole compounds through a microwave-assisted multicomponent reaction in order to access a variety of imidazole compounds with numerous substitution patterns. These compounds will be tested and ultimately help define the structural requirements for allosteric binding to VCP. We will also measure the effect of these imidazoles on VCP activity and cell death.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.