Abstract
The rhizome of Dryopteris crassirhizoma Nakai. (Dryopteridaceae) has been used in traditional medicine in East Asia and has recently been reported to have anticancer, anti-inflammation, and antibacterial activity as well as antiviral activity. Natural phloroglucinols from D. crassirhizoma, dryocrassin ABBA and filixic acid ABA were reported to inhibit influenza virus infection with an inhibitory activity on neuraminidase. In this study, we found that dryocrassin ABBA and filixic acid ABA have an inhibitory activity against the main protease of SARS-CoV-2. Therefore, dryocrassin ABBA and filixic acid ABA exhibited inhibitory activity against SARS-CoV-2 infection in Vero cells dose-dependently using the immunofluorescence-based antiviral assays. Moreover, these compounds inhibited SARS-CoV and MERS-CoV infection, suggesting their broad-spectrum anticoronaviral activity. In addition, a 5-day repeated-dose toxicity study of dryocrassin ABBA and filixic acid ABA suggested that an approximately lethal dose of these compounds in mice was >10 mg/kg. Pharmacokinetic studies of dryocrassin ABBA showed good microsomal stability, low hERG inhibition, and low CYP450 inhibition. In vivo pharmacokinetic properties of dryocrassin ABBA showed a long half-life (5.5–12.6 h) and high plasma exposure (AUC 19.3–65 μg·h/mL). Therefore, dryocrassin ABBA has therapeutic potential against emerging coronavirus infections, including COVID-19.
Highlights
IntroductionIn spite of 8.4 billion doses of coronavirus disease 2019 (COVID-19) vaccines, approximately 274 million confirmed cases of COVID-19 and 5.3 million deaths were reported as of December 2021 by the World Health Organization during the global pandemic [1]
We identified the SARS-CoV-2 Mpro inhibitory activity of natural phloroglucinols, dryocrassin ABBA and filixic acid ABA from the rhizome of D. crassirhizoma, before anticoronaviral activity against SARS-CoV, SARS-CoV-2, and MERS-CoV
We examined the anti-SARS-CoV-2 activity of dryocrassin ABBA and filixic acid ABA
Summary
In spite of 8.4 billion doses of coronavirus disease 2019 (COVID-19) vaccines, approximately 274 million confirmed cases of COVID-19 and 5.3 million deaths were reported as of December 2021 by the World Health Organization during the global pandemic [1]. Effective therapeutics are urgently needed to minimize the cases of critical patients. SARS-CoV-2 as well as SARS-CoV and MERS-CoV, belong to the Coronaviridae family and Betacoronavirus genus [2]. SARS-CoV-2 consists of a 30 kb positive-sense, single-stranded RNA and structural proteins, such as the nucleocapsid, envelope, membrane, and spike proteins.
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