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 apreviously unexposed (`naive') population has resulted in a pandemic with tragic consequences on a globalscale. Although epidemiological data suggests that many individuals infected with COVID-19 are asymptomaticor resolve their infection, a significant number become seriously ill with dysregulated and excessive cytokineproduction 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 improveCOVID-19 associated morbidity and mortality in severe cases. As of this writing, the therapeutic options suchas monoclonal antibodies and remdesivir have questionable value, dexamethasone immunosuppression maybe problematic in COVID-19 patients, and the available vaccine(s) will be limited by production, vaccinationlogistics and citizenry concerns and skepticism (so-called `vaccine hesitancy'). We therefore surmise that accessto a drug with a low side-effect profile which is able to effectively control the cytokine storm, regardless of thestage of disease, remains a high unmet medical need. We intend to fill this gap with a novel class of drugs thatwill 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 theinvolvement of these targets in inflammatory processes, we believe our molecules have the potential to mitigateA key innovation to be implemented as part of ourstrategy is to incorporate both inhibitory activities into a single molecule, in the form ofthat can effectively control hyperinflammation without global immunosuppression. Our lead dualinhibitor, PTUPB, was discovered and characterized by the head of our scientific advisory board, ProfessorBruce Hammock (UC Davis, California).ARDS and hyperinflammation associated with COVID-19.dual sEH/COX-2inhibitors, Recently, PTUPB was demonstrated to an effective suppressor ofchemotherapy-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 accompanyingimmunosuppression 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 disruptprogression of COVID-19 disease and reduce mortality.We propose to 1) screen 50 of our novel moleculesagainst sEH and COX-2 and identify a subset of molecules with a range of potencies against the targetedenzymes, and 2) screen that subset of molecules in unbiased high-throughput analyses to identify novelmolecules with potential to prevent or ameliorate the cytokine storm.
Public Health Relevance Statement: Project Narrative OROX BioSciences has designed and synthesized a chemical library of novel anti-inflammatory/non- immunosuppressive/anti-fibrotic small molecules with dual inhibitory activity targeting soluble epoxide hydrolase and cyclooxygenase-2. These dual inhibitors have the potential to mitigate virally induced cytokine storm and ensuing acute respiratory distress syndrome (ARDS) and acute lung damage believed to be the cause of severe morbidity and death in COVID-19 patients. As a large portion of these proprietary molecules have not been fully characterized, we propose evaluating a selected number of these molecules in in vitro assays designed to characterize their enzyme inhibition profiles and investigate mitigation and suppression of inflammatory cytokine expression responsible for development of ARDS and acute lung injury in COVID-19 patients to select the best performing molecules in preparation for in vivo pharmacology/toxicology studies in a Phase 2 SBIR proposal.
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