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

Pharmaceutics

Min Seong Jang¹  Chul Min Park¹  Hyoung Rae Kim¹  Jong Hwan Song¹  Sunoh Kwon¹  Young-Hee Jin²  Sangeun Jeon³  Jihye Lee³  Seungtaek Kim³ 

[1] Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea;KM Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Korea;Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea;

关键词: cardiotonic steroid;    coronavirus;    MERS;    COVID-19;    antiviral;    pharmacokinetics;   

DOI  :  10.3390/pharmaceutics13111839

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown