Cardiac glycosides and COVID-19: would it be a promising therapeutic approach?

EFTYCHIOS SINIORAKIS SPYRIDON ARVANITAKIS MAXIMILIANOS ELKOURIS About the authors

Abstract

Cardiac glycosides have been found to have an anti-viral effect. This was noted in the past during various epidemics including MERS and SARS. It is due to their inhibitory effect on the Na, K-ATPase membrane pump. Furthermore, they exhibit anti-inflammatory properties. These preclinical observations may prove useful in further clinical utility of these well-known compounds in the current COVID-19 pandemic.

Key words
antiviral effect; cardiac glycosides; COVID-19

In their recent article Trindade et al. (2020)TRINDADE GG, CAXITO SMC, XAVIER AREO, XAVIER MAS & BNANDÃO F. 2020. COVID-19: therapeutic approaches description and discussion. An Acad Bras Cienc 92: e20200466. propose some therapeutic approaches to COVID-19 pandemic, related to the SARS-CoV-2 coronavirus.

Cardiac glycosides (CGS) digoxin and digitoxin merit a privileged position among the antiviral compounds. CGS inhibit the Na, K-ATPase membrane pump, a potent signal transduction pathway and ion-exchanger (Riganti et al. 2011RIGANTI C, CAMPIA I, KOPECKA J, GAZZANO E, DOUBLIER S, ALDIERI E, BOSIA A & GHIGO D. 2011. Pleiotropic effects of cardioactive glycosides. Curr Med Chem 18: 872-885.). RNA viruses use the Na, K-ATPase pump, in order to attach to the host cell membrane and proceed in endocytosis and replication (Amarelle & Lecuona 2018AMARELLE L & LECUONA E. 2018. The antiviral effects of Na, K-ATPase inhibition: A minireview. Int J Mol Sci 19: 2154.). CGS were found in the course of previous viral epidemics including MERS and SARS, to inhibit the signaling properties of the pump, and provoke a host intracellular depletion of potassium (Burkard et al. 2015BURKARD C, VERHEIJE MH, HAAGMANS BL, VAN KUPPEVELD FJ, ROTTIER PJM, BOSCH B-J & DE HAAN CAM. 2015. ATP1A1-mediated Scr signaling inhibits coronavirus entry into host cells. J Virol 89: 4434-4448., Grosso et al. 2017GROSSO F, STOILOV P, LINGWOOD C, BROWN M & COCHRANE A. 2017. Suppression of adenovirus replication by cardiotonic steroids. J Virol 91: e01623-16.). By these mechanisms, CGS inhibited viral transmembrane internalization and viral RNA and pre-RNA splicing necessary for the synthesis of viral proteins, interrupting the replication process (Amarelle et al. 2019AMARELLE L, KATZEN J, SHIGEMURA M, WELCH LC, CAJIGAS H, PETERANDERI C, CELLI D, HEROLD S, LECUONA E & SZNAJDER J. 2019. Cardiac glycosides decrease influenza virus replication by inhibiting cell protein translational machinery. Am J Physiol Lung Cell Mol Physiol 316: L1094-L1106.). Furthermore, CGS possess significant anti-inflammatory properties, in vitro and in vivo, when administered in the course of inflammatory diseases. CGS downregulate various cytokines and activators, such as TNFα, TGFβ and NF-KB ((Yang et al. 2005YANG Q ET AL. 2005. Cardiac glycosides inhibit TNF-alpha / NF-kappa B signaling by blocking recruitment of TNF receptor-associated death to the TNF receptor. Proc Natl Acad Sci USA 102: 9631-9636., Prassas & Diamandis 2008PRASSAS I & DIAMANDIS EP. 2008. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 7: 926-935.).

Given that COVID-19 is characterized by catastrophic proinflammatory cytokine storm in the target organs, an anti-inflammatory action of CGS provokes further investigation. CGS constitute a historical and emblematic treatment in heart failure and supraventricular arrhythmias. Should preclinical observations regarding the antiviral properties of CGS be translated to clinical validation, a new and promising COVID-19 therapeutic approach would emerge.

REFERENCES

  • AMARELLE L & LECUONA E. 2018. The antiviral effects of Na, K-ATPase inhibition: A minireview. Int J Mol Sci 19: 2154.
  • AMARELLE L, KATZEN J, SHIGEMURA M, WELCH LC, CAJIGAS H, PETERANDERI C, CELLI D, HEROLD S, LECUONA E & SZNAJDER J. 2019. Cardiac glycosides decrease influenza virus replication by inhibiting cell protein translational machinery. Am J Physiol Lung Cell Mol Physiol 316: L1094-L1106.
  • BURKARD C, VERHEIJE MH, HAAGMANS BL, VAN KUPPEVELD FJ, ROTTIER PJM, BOSCH B-J & DE HAAN CAM. 2015. ATP1A1-mediated Scr signaling inhibits coronavirus entry into host cells. J Virol 89: 4434-4448.
  • GROSSO F, STOILOV P, LINGWOOD C, BROWN M & COCHRANE A. 2017. Suppression of adenovirus replication by cardiotonic steroids. J Virol 91: e01623-16.
  • PRASSAS I & DIAMANDIS EP. 2008. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 7: 926-935.
  • RIGANTI C, CAMPIA I, KOPECKA J, GAZZANO E, DOUBLIER S, ALDIERI E, BOSIA A & GHIGO D. 2011. Pleiotropic effects of cardioactive glycosides. Curr Med Chem 18: 872-885.
  • TRINDADE GG, CAXITO SMC, XAVIER AREO, XAVIER MAS & BNANDÃO F. 2020. COVID-19: therapeutic approaches description and discussion. An Acad Bras Cienc 92: e20200466.
  • YANG Q ET AL. 2005. Cardiac glycosides inhibit TNF-alpha / NF-kappa B signaling by blocking recruitment of TNF receptor-associated death to the TNF receptor. Proc Natl Acad Sci USA 102: 9631-9636.

Publication Dates

  • Publication in this collection
    28 Oct 2020
  • Date of issue
    2020

History

  • Received
    8 July 2020
  • Accepted
    10 Sept 2020
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