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

研究启动奖：微波合成咪唑化合物以研究 VCP 的变构结合

• 批准号: 2000028
• 负责人: Jacqueline Smith
• 金额: $ 29.55万
• 依托单位: Bowie State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2000028&HistoricalAwards=false
• 关键词: Research; Initiation; Award; Microwave; Synthesis

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.

研究启动奖为历史上黑人学院和大学的初级和中级职业教师提供支持，他们正在建立新的研究项目或重新定向和重建现有的研究项目。预计该奖项将（1）进一步教师的研究能力和有效性，（2）提高研究和教学在家庭机构，和（3）从事更多的本科生从研究经验的代表性不足的群体。Bowie州立大学是一所历史上的黑人学院/大学（HBCU），该项目旨在研究某些酶蛋白的变构结合剂的结构要求，这些酶蛋白在哺乳动物、酵母和植物细胞中维持蛋白质稳态。 该项目将计算化学和生物学与类似的实验室研究相结合。 此外，它的目的是包括本科生和高中学生作为积极的研究人员。合作和指导将在整个项目中进行。PI将与乔治敦大学的另一位研究人员合作，而本科生将在PI的监督下担任高中生的导师。 VCP是在泛素蛋白酶体系统（UPS）中起主要作用的ATP酶。 UPS负责通过蛋白酶体降解未折叠的蛋白质，以缓解细胞应激。一旦被泛素标记，VCP将蛋白质从ER易位到胞质溶胶。已经显示VCP结合剂引起泛素化蛋白的积累，其最终导致细胞死亡。当系统被利用以避免细胞凋亡时，这是有利的。六元环杂环已被证明是ATP竞争性结合剂，因此是非选择性的。 五元环杂环与VCP的变构位点结合，并且具有高度选择性。然而，目前还不清楚变构结合剂的结构要求是什么。我们提出通过微波辅助多组分反应合成咪唑化合物，以获得具有多种取代模式的各种咪唑化合物。 这些化合物将进行测试，并最终帮助确定变构结合VCP的结构要求。 我们还将测量这些咪唑类化合物对VCP活性和细胞死亡的影响。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。