The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview

Abstract

Since being first described more than 60 years ago, Na,K-ATPase has been extensively studied, while novel concepts about its structure, physiology, and biological roles continue to be elucidated. Cardiac glycosides not only inhibit the pump function of Na,K-ATPase but also activate intracellular signal transduction pathways, which are important in many biological processes. Recently, antiviral effects have been described as a novel feature of Na,K-ATPase inhibition with the use of cardiac glycosides. Cardiac glycosides have been reported to be effective against both DNA viruses such as cytomegalovirus and herpes simplex and RNA viruses such as influenza, chikungunya, coronavirus, and respiratory syncytial virus, among others. Consequently, cardiac glycosides have emerged as potential broad-spectrum antiviral drugs, with the great advantage of targeting cell host proteins, which help to minimize resistance to antiviral treatments, making them a very promising strategy against human viral infections. Here, we review the effect of cardiac glycosides on viral biology and the mechanisms by which these drugs impair the replication of this array of different viruses.

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

“…In addition to inhibiting HCMV, cardiac glycosides act as antivirals against a range of clinically important DNA and RNA viruses. This broad-spectrum activity has been attributed to a range of host-directed mechanisms [371].…”

Classical drug digitoxin inhibits influenza cytokine storm, with implications for COVID-19 therapy

“…Finally, since antiviral properties have been reported for digitoxin and other cardiac glycosides, it is limitation of the study that we cannot exclude other antiviral effects by digitoxin from contributing to the reduction in influenza-dependent cytokine concentration [22][23][24] .…”

Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives

“…Cohen et al [23] found that the inhibitory activity of cytomegalovirus replication by convallatoxin was due to a decrease in immediate-early gene expression and that the antiviral potency depends on the structure of cardiac glycosides and their specific interactions with Na + / K + -ATPase. It was also shown that influenza virus replication was impaired by ouabain through the inhibition of viral protein translation and a decrease in the intracellular K + concentration [37]. Finally, Boff et al [38] showed that C10 and C11 inhibited Na + /K + -ATPase, and a reduction in intracellular K + concentration could explain the inhibitory activity of those steps of viral infection.…”

“…Finally, Boff et al [38] showed that C10 and C11 inhibited Na + /K + -ATPase, and a reduction in intracellular K + concentration could explain the inhibitory activity of those steps of viral infection. In summary, the main antiviral mechanisms suggested for both DNA and RNA viruses are decreased transcription of viral genes and impaired synthesis of viral proteins due to interference with the host translational machinery, such as the inhibition of Na + /K + -ATPase [37]. Structural differences among cardenolides, such as the substituents on the aglycone moiety and the number of sugars, may vary and alter their antiviral activity.…”

“…Another suggested possibility is their potential antiviral action, as reported by several authors against adenovirus [18], chikungunya virus [19], coronavirus [20,21], cytomegalovirus [22][23][24], dengue virus [25], herpes virus [26][27][28], HIV [29][30][31], human papillomarivus (HPV) [32], influenza virus [33][34][35], and respiratory syncytial virus [36] replication. The effects of six well-known cardiac glycosides (digoxin, digitoxin, ouabain, convallatoxin, G-strophanthin and lanatoside C) on viral biology and the mechanisms by which they impair the replication of different RNA and DNA viruses were recently compiled [37]. Most of these studies only reported the antiviral activity of cardenolides, and it is required to understand the mechanistic aspects involved and how the compounds really act to further evaluate their potential therapeutic application.…”