Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections

Cardiotonic steroids are steroid-like natural compounds known to inhibit Na<sup>+</sup>/K<sup>+</sup>-ATPase pumps. To develop a broad-spectrum antiviral drug against the emerging coronavirus infection, this study assessed the antiviral properties of these compounds. The acti...

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Autores principales:	Young-Hee Jin, Sangeun Jeon, Jihye Lee, Seungtaek Kim, Min Seong Jang, Chul Min Park, Jong Hwan Song, Hyoung Rae Kim, Sunoh Kwon
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cardiotonic steroid coronavirus MERS COVID-19 antiviral pharmacokinetics Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/cb723872b67d47688aa34a705a37926a
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spelling	oai:doaj.org-article:cb723872b67d47688aa34a705a37926a2021-11-25T18:41:03ZBroad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections10.3390/pharmaceutics131118391999-4923https://doaj.org/article/cb723872b67d47688aa34a705a37926a2021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1839https://doaj.org/toc/1999-4923Cardiotonic steroids are steroid-like natural compounds known to inhibit Na<sup>+</sup>/K<sup>+</sup>-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 (IC<sub>50</sub>, 0.017~0.027 μM); bufalin showed the most potent anti-SARS-CoV and SARS-CoV-2 activity (IC<sub>50</sub>, 0.016~0.019 μM); cinobufotalin and resibufogenin showed comparatively low anti-coronavirus activity (IC<sub>50</sub>, 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.Young-Hee JinSangeun JeonJihye LeeSeungtaek KimMin Seong JangChul Min ParkJong Hwan SongHyoung Rae KimSunoh KwonMDPI AGarticlecardiotonic steroidcoronavirusMERSCOVID-19antiviralpharmacokineticsPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1839, p 1839 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cardiotonic steroid coronavirus MERS COVID-19 antiviral pharmacokinetics Pharmacy and materia medica RS1-441
spellingShingle	cardiotonic steroid coronavirus MERS COVID-19 antiviral pharmacokinetics Pharmacy and materia medica RS1-441 Young-Hee Jin Sangeun Jeon Jihye Lee Seungtaek Kim Min Seong Jang Chul Min Park Jong Hwan Song Hyoung Rae Kim Sunoh Kwon Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections
description	Cardiotonic steroids are steroid-like natural compounds known to inhibit Na<sup>+</sup>/K<sup>+</sup>-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 (IC<sub>50</sub>, 0.017~0.027 μM); bufalin showed the most potent anti-SARS-CoV and SARS-CoV-2 activity (IC<sub>50</sub>, 0.016~0.019 μM); cinobufotalin and resibufogenin showed comparatively low anti-coronavirus activity (IC<sub>50</sub>, 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.
format	article
author	Young-Hee Jin Sangeun Jeon Jihye Lee Seungtaek Kim Min Seong Jang Chul Min Park Jong Hwan Song Hyoung Rae Kim Sunoh Kwon
author_facet	Young-Hee Jin Sangeun Jeon Jihye Lee Seungtaek Kim Min Seong Jang Chul Min Park Jong Hwan Song Hyoung Rae Kim Sunoh Kwon
author_sort	Young-Hee Jin
title	Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections
title_short	Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections
title_full	Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections
title_fullStr	Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections
title_full_unstemmed	Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections
title_sort	broad spectrum antiviral properties of cardiotonic steroids used as potential therapeutics for emerging coronavirus infections
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cb723872b67d47688aa34a705a37926a
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Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections

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