PROJECT ABSTRACT COVID-19 infection is associated with substantial mortality in patients with clinical co-morbidities, including smoking, advanced age and diabetes mellitus. In these patients, COVID-19 infection leads to a hyperinflammatory state producing vascular leak, interstitial edema, hyaline membrane formation and ARDS. COVID-19 patients requiring ICU admission have high circulating levels of IL-6, GM-CSF, MCP and MIP1 (CCL2) cytokines compared to those with uncomplicated illnesses. This hyper-inflammation syndrome, (aka “cytokine storm”) is a prodromal feature of ARDS and multi-organ failure. Bronchoalveolar fluids (BALF) from patients with severe COVID-19 are enriched in CCL2, one of the most potent chemokines driving the recruitment of monocytes into the lung. Of note, cytokine storm is also associated with extensive lung damage in SARS-CoV and MERS- CoV infections, suggesting that innate hyper-inflammation is common to respiratory zoonoses. There is no effective treatment currently available that may be deployed as an intervention to either prevent or ameliorate the cytokine storm of COVID-19. To address this need, our research team is actively engaged in the preclinical development of an optimized lead agent (CDDO-2P-Im, or ‘2P-Im’), a highly potent synthetic triterpenoid that is the most advanced among a class of small molecules recognized as effective modifiers of the host inflammatory response. Our data show that 2P-Im broadly inhibits expression of cytokine networks and pathways underlying hyper-inflammation. In particular, 2P-Im and its related derivatives are potent suppressors of macrophage activation, suppressing the production of MIP1 (CCL2) by human macrophages at picomolar concentrations. 2P- Im is an innovative new drug, with a mechanism of action not shared by any other drug currently under investigation for in use in treating COVID-19. We envision 2P-Im will be provided to patients as an oral agent deployed to prevent macrophage activation syndrome and disrupt progression to the ARDS of COVID-19 disease in high-risk populations. 2P-Im also has potential for use in the outpatient setting as a chemopreventive regimen to reduce risk in first responders, residents living in group settings, and other high-risk groups exposed to COVID-19. Preliminary data demonstrate potent cytoprotective effects in assays of efficacy against Influenza virus A H1N1 and Influenza virus A H3N2. Through partnership between Triterpenoid Therapeutics (TTX) and the Texas Biomedical Research Institute, we will pursue full-scale, IND-enabling efficacy studies in established mouse models of COVID-19. Specifically, we will define the capacity of 2P-Im to prevent the cytopathic effects of SARS-CoV-2 in established, validated in vitro models of COVID-19 (Aim 1); and demonstrate the in vivo efficacy of 2P-Im against SARS-CoV-2 induced inflammation and capacity to promote survival in the established K18-hACE2 mouse model of COVID-19 (Aim 2). The proposed pl...