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.