Preclinical studies to establish the combination of apoA-I mimetic peptides and statins as novel therapy for COVID-19

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PROJECT SUMMARY/ABSTRACT The SARS-CoV-2 pandemic emphasizes the urgent need to determine pathways that can be targeted by novel antivirals. This proposal describes the use of the combination of apoA-I mimetics with statins as novel therapy for COVID-19. SARS-CoV-2 utilizes mitochondria to replicate in lung epithelial cells. Mitochondrial reactive oxygen species (mito-ROS) induce alterations of lipids, membranes and redox sensitive proteins and ultimately viral replication. Thus, we hypothesized that the antioxidant ApoA-I mimetic peptide 4F, that targets lipids, mito-ROS and redox pathways, has antiviral activity against SARS-CoV-2. We confirmed that 4F not only has antiviral activity against SARS-CoV-2 but also has anti-inflammatory effects in epithelial cells that may alleviate lung injury in COVID-19. Importantly, prior studies have shown that 4F and statins may have major additive in vivo effects on altered lipids, oxidative stress and inflammation that are instigators of cardiovascular disease. Human studies suggest that statin use was associated with a lower risk of developing severe COVID-19. Both statins and 4F attenuate activation of the Toll like Receptor (TLR)-CD147-NF-κB pathways, which are key inflammatory pathways in coronavirus infections. We hypothesize that the combination of 4F and statins has antiviral activity against SARS-CoV-2 in lung epithelial cells and anti-inflammatory activity in lung epithelial cells, macrophages and vascular endothelial cells by attenuating the redox sensitive TLR-CD147-NF-κB proviral and proinflammatory pathway. Thus, in Aim 1 of this proposal and using an air-liquid interface (ALI) culture of primary airway epithelial cells, and cell lines in combination with viral and immune assays, we will determine the mechanisms how the combination of 4F with atorvastatin attenuates aberrant activation of the TLR-CD147-NF-κB pathway as a novel mechanism that drives viral replication and associated inflammatory responses in SARS-CoV-2 infected lung cells. Given that vascular dysfunction is a possible mechanism of chronic post-infectious sequalae of COVID-19, in Aim 2 of this proposal and using an established ex vivo model of atherogenesis and vascular dysfunction and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients in combination with immune assays, we will determine whether 4F and atorvastatin attenuate aberrant activation of the TLR-CD147-NF-κB pathway in macrophages from COVID-19 patients that interact ex vivo with endothelial cells to drive proinflammatory proatherogenic responses. Our independent aims will complement each other and will advance the use of the combination of apoA-I mimetic peptides and statins as novel therapy for COVID-19. This work is innovative, interdisciplinary, public health-oriented, and directly addresses the goals of funding opportunity.