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

Salerno, José Alexandre; Torquato, Thayana; Temerozo, Jairo R.; Goto-Silva, Livia; Mendes, Mayara; Sacramento, Carolina Q.; Fintelman-Rodrigues, Natalia; Vitoria, Gabriela; Souza, Leticia; Ornelas, Isis; Veríssimo, Carla; Karmirian, Karina; Pedrosa, Carolina; Dias, Suelen da Silva Gomes; Soares, Vinicius Cardoso; Aragão, Luiz Guilherme HS; Puig-Pijuan, Teresa; Salazar, Vinícius W.; Dariolli, Rafael; Biagi, Diogo; Furtado, Daniel Rodrigues; Borges, Helena L.; Bozza, Patrícia; Guimarães, Marília Zaluar; Souza, Thiago Moreno L.; Rehen, Stevens K.

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.