Old drugs, novel uses: combination of ivermectin and hemin as a promising treatment against SARS-CoV-2 infection

SOFIA LAGE-VICKERS; ROCIO SENIUK ; ANA PAULA AREVALO; AYELEN TORO; ALAN MINOTTI; JUAN BIZZOTTO; ELBA VAZQUEZ; MARTINA CRISPO; PABLO SANCHIS; GASTON PASCUAL; JAVIER COTIGNOLA; GERALDINE GUERON

Virtual

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2021

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel virus that is the causal agent of the Coronavirus disease 2019 (COVID-19). Given the urgent need for drugs to halt COVID-19 infection, one of the most valuable strategies is drug repurposing. The aim of this study was to analyze the antiviral effect of hemin and ivermectin (IVM), two drugs approved by Food and Drug Administration (FDA). The effect of hemin and IVM was evaluated in human pulmonary epithelial cells (A549 cell line). We evaluated the expression of genes related to SARS-CoV-2 infection, antiviral genes and anti-inflammatory genes by RT-qPCR. First, we established the optimal doses of hemin (80 uM) and IVM (10 uM) in this experimental model. Then, we cultured A549 cells with hemin and IVM, alone or in combination during different timepoints. We found that IVM treatmentresulted in an increased expression of MX1 (p<0.001), an antiviral response gene against a great diversity of viruses. Moreover, in this in vitro model, hemin induced the expression of HMOX1 (p<0.001), a gene that encodes for the anti-inflammatory protein HO-1, and this effect was enhanced when hemin was combined with IVM (p<0.001). Concerning the proteins associated with virus entry into the host cell, we found that both IVM and hemin decreased the expression of BSG (p<0.01), a membrane receptor that facilitates SARS-CoV-2 entry, and the combination of these drugs increased the expression of ADAM17 (p<0.001), whose activity is related to viral entry inhibition. Finally, we mimicked viral infection using Poly(I:C), a synthetic analog of viraldouble-stranded RNA. Poly(I:C) treatment increased NF-κB and IRF3 expressions, validating the Poly(I:C) responsiveness of A549 cells. In this viral simulation context, IVM treatment also boosted MX1 expression (p<0.05) and hemin induced HMOX1 (p<0.001). Altogether, our results ascertain the potential antiviral action of hemin and IVM combination.