Research Initiation Award: Novel Imidazole Compounds to Investigate the Unfolded Protein Response (UPR)

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Catalyst Projects provide support for Historically Black Colleges and Universities to work towards establishing research capacity of faculty to strengthen science, technology, engineering and mathematics undergraduate education and research. It is expected that the award will further the faculty member's research capability, improve research and teaching at the institution, and involve undergraduate students in research experiences. The award to Bowie State University has potential to broader impact in a number of areas. This proposal aims to synthesize a library of compounds with subtle structural changes to determine how a non-functional binding site on a protein can affect the protein?s function. Gaining an understanding how small molecule affect this protein can help scientists understand and control cell death. Undergraduate students will gain research experience in organic synthesis and biochemistry. The cell has many adaptive mechanisms used for the cellular repair during endoplasmic reticulum (ER) stress. If proteostasis is not re-established, unfolded proteins are tagged for clearance through the ubiquitin-proteasome system (UPS). Aberrant cells have been shown to exploit these prosurvival mechanisms as a way to circumvent cell death. However proteasome disruption leads to cell death. Valosin-containing protein (VCP) is a key component of the UPS which may be targeted to investigate its role in proteostasis. Small molecule heterocycles such as imidazoles have the potential to allosterically bind to VCP to disrupt the UPS in rogue cells. The utilization of a two-step synthesis of a library of novel imidazole compounds through microwave-assisted multicomponent reactions will allow a variety of imidazole compounds to be rapidly synthesized. Ultimately these compounds will be used to identify the structural features which are key for allosteric binding to VCP.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.