Na+/K+-ATPase as a Target of Cardiac Glycosides for the Treatment of SARS-CoV-2 Infection

Souza, Kauê Francisco Corrêa Souza e; Moraes, Bianca Portugal Tavares de; Paixão, Izabel Christina Nunes de Palmer; Burth, Patrícia; Silva, Adriana Ribeiro; Gonçalves-de-Albuquerque, Cassiano Felippe

doi:10.3389/fphar.2021.624704

Cited by 17 publications

(11 citation statements)

References 168 publications

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“…Most probably, it will not be much different from that reported on other coronaviruses. This has been suggested as well by Souza et al [71], in a review article focused on CG action against SARS-CoV-2. The most probable mechanism of the anti-Covid-19 action of CGs is the inhibition of the nuclear factor kappa B (NF-kB) through Src signaling linked to NKA.…”

Section: Disruption Of the Early Stages Of The Viral Life Cyclesupporting

confidence: 52%

Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses

et al. 2021

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Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

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Section: Disruption Of the Early Stages Of The Viral Life Cyclesupporting

confidence: 52%

Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses

et al. 2021

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“…This is somehow surprising considering that this pump is responsible for a basic relevant function, namely the maintenance of the physiological electrolyte gradient and regulation of the influx/efflux of both sodium and potassium across the cellular membranes. In addition, this pump plays a relevant role in relaying cardiotonic steroid-binding-induced signals into cells [96] and, most importantly, in edema clearance [97]. Most attention have been given to the upstream renin-angiotensinaldosterone system (RAAS).…”

Section: Discussionmentioning

confidence: 99%

Nonthyroidal illness syndrome (NTIS) in severe COVID-19 patients: role of T3 on the Na/K pump gene expression and on hydroelectrolytic equilibrium

et al. 2021

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Background Nonthyroidal Illness Syndrome (NTIS) can be detected in many critical illnesses. Recently, we demonstrated that this condition is frequently observed in COVID-19 patients too and it is correlated with the severity the disease. However, the exact mechanism through which thyroid hormones influence the course of COVID-19, as well as that of many other critical illnesses, is not clear yet and treatment with T4, T3 or a combination of both is still controversial. Aim of this study was to analyze body composition in COVID-19 patients in search of possible correlation with the thyroid function. Methods and findings We report here our experience performed in 74 critically ill COVID-19 patients hospitalized in the intensive care unit (ICU) of our University Hospital in Rome. In these patients, we evaluated the thyroid hormone function and body composition by Bioelectrical Impedance Analysis (BIA) during the acute phase of the disease at admission in the ICU. To examine the effects of thyroid function on BIA parameters we analyzed also 96 outpatients, affected by thyroid diseases in different functional conditions. We demonstrated that COVID-19 patients with low FT3 serum values exhibited increased values of the Total Body Water/Free Fat Mass (TBW/FFM) ratio. Patients with the lowest FT3 serum values had also the highest level of TBW/FFM ratio. This ratio is an indicator of the fraction of FFM as water and represents one of the best-known body-composition constants in mammals. We found an inverse correlation between FT3 serum values and this constant. Reduced FT3 serum values in COVID-19 patients were correlated with the increase in the total body water (TBW), the extracellular water (ECW) and the sodium/potassium exchangeable ratio (Nae:Ke), and with the reduction of the intracellular water (ICW). No specific correlation was observed in thyroid patients at different functional conditions between any BIA parameters and FT3 serum values, except for the patient with myxedema, that showed a picture similar to that seen in COVID-19 patients with NTIS. Since the Na+/K+ pump is a well-known T3 target, we measured the mRNA expression levels of the two genes coding for the two major isoforms of this pump. We demonstrated that COVID-19 patients with NTIS had lower levels of mRNA of both genes in the peripheral blood mononuclear cells (PBMC)s obtained from our patients during the acute phase of the disease. In addition, we retrieved data from transcriptome analysis, performed on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)s treated with T3 and we demonstrated that in these cells T3 is able to stimulate the expression of these two genes in a dose-dependent manner. Conclusions In conclusion, we demonstrated that measurement of BIA parameters is a useful method to analyze water and salt retention in COVID-19 patients hospitalized in ICU and, in particular, in those that develop NTIS. Our results indicate that NTIS has peculiar similarities with myxedema seen in severe hypothyroid patients, albeit it occurs more rapidly. The Na+/K+ pump is a possible target of T3 action, involved in the pathogenesis of the anasarcatic condition observed in our COVID-19 patients with NTIS. Finally, measurement of BIA parameters may represent good endpoints to evaluate the benefit of future clinical interventional trials, based on the administration of T3 in patients with NTIS.

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“…Numerous existing drugs have been repurposed for treating COVID-19 disease, such as chloroquine, remdesivir, favipiravir, and umifenovir [30]. However, currently there is no effective treatment that has been approved by regulators [36]. Chloroquine, an antimalarial drug, possesses antiviral activity, including against coronaviruses, and has been considered as a possible antiviral drug for SARS-CoV-2 and been tested against COVID-19 in China.…”

Section: Identified Medicinal Plants and Their Active Compounds Against Sars-cov-2mentioning

confidence: 99%

“…Some cardiac glycosides have shown antiviral activity through inhibition of NKA and activation of tyrosine kinase (Src). Src regulates nuclear factor kappa B (NFkB), which is the important transcription factor for SARS-CoV-2 [36].…”

Section: Identified Medicinal Plants and Their Active Compounds Against Sars-cov-2mentioning

confidence: 99%

Leveraging knowledge of Asian herbal medicine and its active compounds as COVID-19 treatment and prevention

Liana

Phanumartwiwath

2021

J Nat Med

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The outbreak of COVID-19 disease has led to a search for effective vaccines or drugs. However, insufficient vaccine supplies to meet global demand and no effective approved prescribed drugs for COVID-19 have led some people to consider the use of alternative or complementary medicines, such as traditional herbal medicine. Medicinal plants have various therapeutic properties that depend on the active compounds they contain. Obviously, herbal medicine has had an essential role in treatment and prevention during COVID-19 outbreak, especially in Asian cultures. Hence, we reviewed the uses of herbal medicine in Asian cultures and described the prominent families and species that are sources of antiviral agents against COVID-19 on the basis of case reports, community surveys, and guidelines available in the literature databases. Antiviral efficacy as determined in laboratory testing was assessed, and several promising active compounds with their molecular targets in cell models against SARS-CoV-2 viral infection will be discussed. Our review findings revealed the highly frequent use of Lamiaceae family members, Zingiber officinale, and Glycyrrhiza spp. as medicinal sources for treatment of COVID-19. In addition, several plant bioactive compounds derived from traditional herbal medicine, including andrographolide, panduratin A, baicalein, digoxin, and digitoxin, have shown potent SARS-CoV-2 antiviral activity as compared with some repurposed FDA-approved drugs. These commonly used plants and promising compounds are recommended for further exploration of their safety and efficacy against COVID-19.

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Na+/K+-ATPase as a Target of Cardiac Glycosides for the Treatment of SARS-CoV-2 Infection

Cited by 17 publications

References 168 publications

Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses

Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses

Nonthyroidal illness syndrome (NTIS) in severe COVID-19 patients: role of T3 on the Na/K pump gene expression and on hydroelectrolytic equilibrium

Leveraging knowledge of Asian herbal medicine and its active compounds as COVID-19 treatment and prevention

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