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

催化剂项目支持历史悠久的黑人学院和大学致力于建立教职员工的研究能力，以加强科学、技术、工程和数学本科教育和研究。预计该奖项将进一步提高教职员工的研究能力，改善学院的研究和教学，并让本科生参与研究经验。授予鲍伊州立大学的奖项有可能在许多领域产生更广泛的影响。这项提议旨在合成一个具有微妙结构变化的化合物文库，以确定蛋白质上的非功能结合部位如何影响蛋白质的功能？S功能。了解小分子是如何影响这种蛋白质的，可以帮助科学家理解和控制细胞死亡。本科生将获得有机合成和生物化学方面的研究经验。在内质网(ER)应激过程中，细胞具有许多用于细胞修复的适应性机制。如果蛋白平衡没有重新建立，未折叠的蛋白被标记为通过泛素-蛋白酶体系统(UPS)清除。异常细胞已被证明利用这些生存机制作为规避细胞死亡的一种方式。然而，蛋白酶体的破坏会导致细胞死亡。含有Valosin的蛋白(VCP)是UPS的一个关键成分，可能是研究其在蛋白平衡中的作用的靶点。小分子杂环，如咪唑类化合物，有可能与VCP变构结合，破坏流氓细胞中的UPS。通过微波辅助多组分反应两步合成新型咪唑化合物文库，将使各种咪唑化合物能够快速合成。最终，这些化合物将被用来确定变构结合VCP.的关键结构特征。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.