Abstract

Introduction: Polymerase delta-interacting protein-2 (Poldip2) mediates inflammation and endothelial permeability. Infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) results in lung inflammation and edema. We therefore hypothesized that Poldip2 inhibition may preserve endothelial barrier function and reduce inflammation in response to SARS-CoV-2 infection. Methods: Humanized ACE2 C57/Bl6 male and female mice were intranasally inoculated with SARS-CoV-2 or PBS vehicle. Poldip2 inhibition was achieved using BC-1215, an anti-inflammatory agent that targets Poldip2 based on molecular docking modeling. Mice received daily i.p. injections of 100 μg BC-1215 or saline for 7 days. Bronchoalveolar lavage (BAL) fluid was collected at 7 days for cell counts and ELISA determination of cytokine production. Lungs were harvested for qPCR. Results: Initial dosing experiments established a SARS-CoV-2 infection model and indicated that 4x10 5 infectious units of SARS-CoV-2 increased viral N2 copy number to 1.1x10 6 in the lung, but not heart and liver. The SARS-CoV-2 increase in CXCL1 mRNA in the lung was reduced by BC-1215 (5.9x10 -10 vs 7.6x10 -11 , P<0.05). TNF-α and MCP1 mRNA levels also trended down after BC-1215 treatment (5.9x10 -10 vs 2.1x10 -10 and 1.3x10 -09 vs 6.6x10 -10 , respectively). In BAL fluid, SARS-CoV-2-induced TNF-α (16.7pg/mL vs 6.0pg/mL, P<0.05) and IFN- γ (619.3pg/mL vs 1703.7pg/mL, P<0.05) levels were reduced by BC-1215. Protein accumulation and cell counts in BAL also trended down after BC-1215 treatment (protein 1325 mg/mL vs 805 mg/mL, cell number 202,833 vs 117,860). Conclusion: Inhibition of Poldip2 by BC-1215 treatment reduced TNF-α, CXCL1, IFN-γ in SARS-CoV-2 infected mice, suggesting that BC-1215 is a promising agent for treatment of COVID-19.