Inhibition of SARS-CoV-2 infection in human cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoskeleton architecture and contractility

Salerno, J. A.; Torquato, T.; Temerozo, J. R.; Goto-Silva, L.; Mendes, M. A.; Sacramento, C. Q.; Fintelman-Rodrigues, N.; Vitoria, G.; Souza, L. R. Q.; Ornelas, I. M.; Verissimo, C.; Karmirian, K.; Pedrosa, C. d. S. G.; Dias, S. d. S. G.; Soares, V. C.; Aragao, L. G. H. S.; Puig-Pijuan, T.; Salazar, V. W.; Dariolli, R.; Biagi, D.; Furtado, D. R.; Borges, H. L.; Bozza, P. T.; Guimaraes, M. Z. P.; Souza, T. M. L.; Rehen, S.

doi:10.1101/2021.02.20.432092

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bioRxiv · 10.1101/2021.02.20.432092

Inhibition of SARS-CoV-2 infection in human cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoskeleton architecture and contractility

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Abstract

Heart dysfunction, represented by conditions such as myocarditis and arrhythmia, has been reported in COVID-19 patients. Therapeutic strategies focused on the cardiovascular system, however, remain scarce. The Sigma-1 receptor (S1R) has been recently proposed as a therapeutic target because its inhibition reduces SARS-CoV-2 replication. To investigate the role of S1R in SARS-CoV-2 infection in the heart, we used human cardiomyocytes derived from induced pluripotent stem cells (hiPSC-CM) as an experimental model. Here we show that the S1R antagonist NE-100 decreases SARS-CoV-2 infection and viral replication in hiPSC-CMs. Also, NE-100 reduces cytokine release and cell death associated with infection. Because S1R is involved in cardiac physiology, we investigated the effects of NE-100 in cardiomyocyte morphology and function. We show that NE-100 compromises cytoskeleton integrity and reduces beating frequency, causing contractile impairment. These results show that targeting S1R to challenge SARS-CoV-2 infection may be a useful therapeutic strategy but its detrimental effects in vivo on cardiac function should not be ignored.

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Salerno, J. A., Torquato, T., Temerozo, J. R., Goto-Silva, L., Mendes, M. A., Sacramento, C. Q., Fintelman-Rodrigues, N., Vitoria, G., Souza, L. R. Q., Ornelas, I. M., Verissimo, C., Karmirian, K., Pedrosa, C. d. S. G., Dias, S. d. S. G., Soares, V. C., Aragao, L. G. H. S., Puig-Pijuan, T., Salazar, V. W., Dariolli, R., Biagi, D., Furtado, D. R., Borges, H. L., Bozza, P. T., Guimaraes, M. Z. P., Souza, T. M. L., Rehen, S.. 2021-02-21. Inhibition of SARS-CoV-2 infection in human cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoskeleton architecture and contractility. https://doi.org/10.1101/2021.02.20.432092

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