Project Summary/Abstract The World Health Organization has reported over 216 million confirmed cases of COVID-19 infections and over 4.5 million deaths world-wide as of August 31, 2021. The rapid introduction of this new coronavirus into a previously unexposed (`naive') population has resulted in a pandemic with tragic consequences on a global scale. Although epidemiological data suggests that many individuals infected with COVID-19 are asymptomatic or resolve their infection, a significant number become seriously ill with dysregulated and excessive cytokine production that can result in a pathological condition termed Cytokine Storm (CS) or Cytokine Release Syndrome (or CRS). These results suggest that treatment of hyperinflammation to prevent cytokine storm could improve COVID-19 associated morbidity and mortality in severe cases. As of this writing, the therapeutic options such as monoclonal antibodies and remdesivir have questionable value, dexamethasone immunosuppression may be problematic in COVID-19 patients, and the available vaccine(s) will be limited by production, vaccination logistics and citizenry concerns and skepticism (so-called `vaccine hesitancy'). We therefore surmise that access to a drug with a low side-effect profile which is able to effectively control the cytokine storm, regardless of the stage of disease, remains a high unmet medical need. We intend to fill this gap with a novel class of drugs that will reduce both the morbidity and mortality associated with the cytokine storm. We have designed and synthesized novel small molecules that are `dual' inhibitors of soluble epoxide hydrolase (sEH) and selected secondary anti-inflammatory targets including cyclooxygenase-2 (COX-2). Given the involvement of these targets in inflammatory processes, we believe our molecules have the potential to mitigate A key innovation to be implemented as part of our strategy is to incorporate both inhibitory activities into a single molecule, in the form of that can effectively control hyperinflammation without global immunosuppression. Our lead dual inhibitor, PTUPB, was discovered and characterized by the head of our scientific advisory board, Professor Bruce Hammock (UC Davis, California). ARDS and hyperinflammation associated with COVID-19. dual sEH/COX-2 inhibitors, Recently, PTUPB was demonstrated to an effective suppressor of chemotherapy-induced cytokine storm. This work has demonstrated that in contrast to conventional anti- inflammatory drugs, this dual sEH/COX-2 inhibitors can prevent the cytokine storm without the accompanying immunosuppression that may result from use of a potent glucocorticoid such as dexamethasone. We hypothesize that our molecules can be used in early intervention, as opposed to steroids, to disrupt progression of COVID-19 disease and reduce mortality. We propose to 1) screen 50 of our novel molecules against sEH and COX-2 and identify a subset of molecules with a range of potencies against the targeted enzyme...