Photoelectrocyclizations to Virulence Inhibiting Natural Product

光化学电环化的补充资金申请 毒力抑制天然产物 项目摘要 R01 GM132531摘要。关于抗药性日益流行的报道 细菌已经导致了对发展新战略的迫切需要 抗菌剂。这个应用程序提供了这样一种方法。我们计划利用 加强对沟通在细菌毒力中所起作用的理解 开发能够阻断这种现象的小分子。具体地说，这项工作的重点是 关于开发具有结构和生物价值的小分子天然产物的研究 作为毒力抑制剂的discorhabdin和abietane家族。作为我们努力的一部分 产生这些家族我们正在开发以光化学为中心的新化学 包括对映体选择性转化的电环化反应。 请求： 我们正在申请资金，为Drue Domagala女士执行 2021年夏天雷尼尔组的研究。多玛加拉女士将执行 选择性TLR-PROTAC系统作为靶标手段的发展研究 对包括冠状病毒感染和细菌感染在内的疾病的免疫反应。 摘要： 已知有10种结构上相关的Toll样受体(TLR) 人类。TLR参与对损伤和侮辱的免疫反应，通过其 识别病原体的能力(脂肽和蛋白质、RNA、脂类、鞭毛、DNA、小分子 分子等)。对这些病原体的免疫反应，在必要时，可以成为 不受控制。这些不幸的事件发生在几乎所有的疾病中，当它 这会不会有问题。我们认为，TLR选择性抑制剂的开发 可能会改善对包括细菌感染和冠状病毒感染在内的疾病的反应。 我们建议合成和开发由已知的吡唑组成的PROTAC抑制剂 与E3连接酶抑制剂对各种TLR具有选择性的配体 沙利度胺。

Supplemental Funding Request for Photochemical Electrocyclizations to Virulence Inhibiting Natural Products Project Summary Abstract of R01 GM132531. Reports of the increasing prevalence of drug resistant bacteria has resulted in a vital need for new strategies for the development of antimicrobials. This application offers such an approach. We plan to take advantage of the enhanced understanding of the role that communication plays in bacterial virulence to develop small molecules that interrupt this phenomenon. Specifically, this work is focused on developing structurally and biologically interesting small molecule natural products from the discorhabdin and abietane families as virulence inhibitors. As part of our effort to generate these families we are developing new chemistry centered around photochemical electrocyclization reactions including enantioselective transformations. Request: We are requesting funds for salary support for Ms. Drue Domagala to carry out research in the Rainier group for the summer of 2021. Ms. Domagala will be carrying out research on the development of selective TLR-PROTAC systems as a means of targeting the immune response to diseases including COVID and bacterial infections. Summary: There are 10 structurally related Toll-Like Receptors (TLR’s) that are known in humans. The TLR’s are involved in the immune response to injury and insult through their ability to recognize pathogens (lipopeptides and proteins, RNA, lipids, flagellin, DNA, small molecules, etc.). The immune response to these pathogens, while necessary, can become uncontrolled. These unfortunate events happen across nearly all diseases and when it does it can problematic. We propose that the development of selective inhibitors of TLR’s may lead to the improved response to disease including bacterial infections and COVID. We propose to synthesize and develop PROTAC inhibitors that consist of known pyrazole ligands that have shown selectivity for various TLR’s with the E3 ligase inhibitor thalidomide.