References supporting ATPases Ion Pumps as drug targets for CoViD

Diabetes Res Clin Pract. 2020 Sep;167:108282. doi: 10.1016/j.diabres.2020.108282. Epub 2020 Jun 25.

A proposed mechanism for the possible therapeutic potential of Metformin in COVID-19

Zohreh Esam 1


The whole world is facing a tough time these days struggling against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is not any specific effective drug for this viral infection. Thus, we are trying to treat patients with non-specific drug cocktails. Metformin, as a strong base, a potential regulator of Vacuolar ATPase (V-ATPase) and endosomal Na+/H+ exchangers (eNHEs), additionally a regenerative agent for lung fibrosis, seems to be beneficial for patients in acute, chronic and recovery phases of COVID-19.



Int J Mol Sci. 2018 Aug; 19(8): 2154.

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

Luciano Amarelle1,2 and Emilia Lecuona1,*


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.




Study finds existing drugs that could treat COVID-19

Posted by Valerie Walters on Jul 29, 2020 8:00 am

A Nature study authored by a global team of scientists at Sanford Burnham Prebys Medical Discovery Institute, has identified 21 existing drugs that stop the replication of SARS-CoV-2, the virus that causes COVID-19.

The study reported a high-throughput analysis of approximately 12,000 known drugs evaluated for activity against SARS-CoV-2 replication, revealing approximately 100 known drugs with antiviral activities. Of these, 21 drugs were determined to be effective at concentrations that could be safely achieved in patients. Several major target classes were found to be enriched for activity in this analysis, including ion channels, GPCRs, proteases, and kinases. Notably, four of these compounds were found to work synergistically with remdesivir, a current standard-of-care treatment for COVID-19. The pharmacokinetic properties of each individual compound, including factors such as serum protein binding and bioavailability in the lung, will impact potential in vivo antiviral efficacy.



Adv Ther. 2017; 34(5): 1070–1086.

A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors

Li-Yuan Yu,1 Lu-Ning Sun,1 Xue-Hui Zhang,2 Yue-Qi Li,1 Lei Yu,1 Zi-Qing-Yun Yuan,1 Ling Meng,1 Hong-Wen Zhang,1 and Yong-Qing Wangcorresponding author1,2


Proton pump inhibitors (PPIs) are known as a class of pharmaceutical agents that target H+/K+-ATPase, which is located in gastric parietal cells. PPIs are widely used in the treatment of gastric acid-related diseases including peptic ulcer disease, erosive esophagitis and gastroesophageal reflux disease, and so on. These drugs present an excellent safety profile and have become one of the most commonly prescribed drugs in primary and specialty care. Except for gastric acid-related diseases, PPIs can also be used in the treatment of Helicobacter pylori infection, viral infections, respiratory system diseases, cancer and so on. Although PPIs are mainly used short term in patients with peptic ulcer disease, nowadays these drugs are increasingly used long term, and frequently for a lifetime, for instance in patients with typical or atypical symptoms of gastroesophageal reflux disease and in NSAID or aspirin users at risk of gastrotoxicity and related complications including hemorrhage, perforation and gastric outlet obstruction. Long-term use of PPIs may lead to potential adverse effects, such as osteoporotic fracture, renal damage, infection (pneumonia and clostridium difficile infection), rhabdomyolysis, nutritional deficiencies (vitamin B12, magnesium and iron), anemia and thrombocytopenia. In this article, we will review some novel uses of PPIs in other fields and summarize the underlying adverse reactions.



mBio. 2016 May-Jun; 7(3): e00693-16.

Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection

Alison W. Ashbrook,a,b Anthony J. Lentscher,b,c Paula F. Zamora,b,c Laurie A. Silva,a,b Nicholas A. May,d Joshua A. Bauer,e,f Thomas E. Morrison,d and Terence S. Dermodycorresponding authora,b,c


Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We conducted a high-throughput, chemical compound screen that identified digoxin, a cardiac glycoside that blocks the sodium-potassium ATPase, as a potent inhibitor of CHIKV infection. Treatment of human cells with digoxin or a related cardiac glycoside, ouabain, resulted in a dose-dependent decrease in infection by CHIKV. Inhibition by digoxin was cell type-specific, as digoxin treatment of either murine or mosquito cells did not diminish CHIKV infection. Digoxin displayed antiviral activity against other alphaviruses, including Ross River virus and Sindbis virus, as well as mammalian reovirus and vesicular stomatitis virus. The digoxin-mediated block to CHIKV and reovirus infection occurred at one or more postentry steps, as digoxin inhibition was not bypassed by fusion of CHIKV at the plasma membrane or infection with cell surface-penetrating reovirus entry intermediates. Selection of digoxin-resistant CHIKV variants identified multiple mutations in the nonstructural proteins required for replication complex formation and synthesis of viral RNA. These data suggest a role for the sodium-potassium ATPase in promoting postentry steps of CHIKV replication and provide rationale for modulation of this pathway as a broad-spectrum antiviral strategy.



Virology. 2007 Sep 30;366(2):340-8. doi: 10.1016/j.virol.2007.05.001. Epub 2007 Jun 1.

Inhibitors of the sodium potassium ATPase that impair herpes simplex virus replication identified via a chemical screening approach

Allen W Dodson 1, Travis J Taylor, David M Knipe, Donald M Coen


Small molecules can provide valuable tools to investigate virus biology. We developed a chemical screening approach to identify small molecule inhibitors of poorly understood, pre-early gene expression steps in herpes simplex virus infection, using green fluorescent protein fused to an early protein. Our assay identified ouabain, a cardiac glycoside. Ouabain reversibly decreased viral yield by 100-fold without affecting cellular metabolic activity in an overnight assay. The antiviral potencies of other cardiac glycosides correlated with their potencies against the known target of these compounds, the cellular sodium potassium ATPase. Ouabain had a reduced effect if added 8 h post-infection. It did not inhibit viral attachment or entry, but did reduce the expression of viral immediate-early and early genes by at least 5-fold. Collectively, these results implicate a cellular target that was hitherto not considered important for a stage of HSV replication prior to viral gene expression.