Abstract
Cardiotonic steroids are steroid-like natural compounds known to inhibit Na+/K+-ATPase pumps. To develop a broad-spectrum antiviral drug against the emerging coronavirus infection, this study assessed the antiviral properties of these compounds. The activity of seven types of cardiotonic steroids against the MERS-CoV, SARS-CoV, and SARS-CoV-2 coronavirus varieties was analyzed using immunofluorescence antiviral assay in virus-infected cells. Bufalin, cinobufagin, and telocinobufagin showed high anti-MERS-CoV activities (IC50, 0.017~0.027 μM); bufalin showed the most potent anti-SARS-CoV and SARS-CoV-2 activity (IC50, 0.016~0.019 μM); cinobufotalin and resibufogenin showed comparatively low anti-coronavirus activity (IC50, 0.231~1.612 μM). Differentially expressed genes in Calu3 cells treated with cinobufagin, telocinobufagin, or bufalin, which had high antiviral activity during MERS-CoV infection were analyzed using QuantSeq 3′ mRNA-Seq analysis and data showed similar gene expression patterns. Furthermore, the intraperitoneal administration of 10 mg/kg/day bufalin, cinobufagin, or digitoxin induced 100% death after 1, 2, and 4 days in 5-day repeated dose toxicity studies and it indicated that bufalin had the strongest toxicity. Pharmacokinetic studies suggested that telocinobufagin, which had high anti-coronavirus activity and low toxicity, had better microsomal stability, lower CYP inhibition, and better oral bioavailability than cinobufagin. Therefore, telocinobufagin might be the most promising cardiotonic steroid as a therapeutic for emerging coronavirus infections, including COVID-19.
Highlights
Severe acute respiratory infectious diseases have been induced by zoonotic betacoronaviruses such as severe acute respiratory syndrome (SARS)-CoV, MERS-CoV, and SARS-CoV-2 [1]
This study focused on the antiviral properties of cardiotonic steroids, which are natural compounds with a steroid-like structure
This study aimed to identify an optimal candidate cardiotonic steroid that shows effective broad-spectrum antiviral activity against emerging coronaviruses and high availability for clinical application
Summary
Severe acute respiratory infectious diseases have been induced by zoonotic betacoronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2 [1]. Since the outbreak of severe acute respiratory syndrome (SARS) in 2002, highly pathogenic and transmissible coronavirus disease, MERS and COVID-19 have threatened public health and welfare. Even though vaccination against COVID-19 is extensively underway, the number of confirmed cases worldwide is over 200 million with up to 4.3 million deaths till August 2021 [2], indicating that the pandemic is not yet abating. Remdesivir, the first-in-class antiviral drug of choice for COVID-19, has been clinically used for treating COVID-19 patients. The development of best-in-class broad-spectrum antivirals which might be able to terminate the current pandemic is still needed.
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