Abstract
The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective in a challenge study using hamsters as disease model.
Highlights
To further evaluate the efficacy of these promising compounds in animal models, we developed a challenge assay with hamsters and found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective against SARS-CoV-2 infection
We found that the aqueous extracts of herbs from Lamiaceae (Perilla frutescens), Mentheae (Mentha haplocalyx), Asteraceae (Taraxacum mongolicum, Tussilago farfara, Chrysanthemum morifolium), Theaceae (Camellia sinensis), Lamiaceae (Prunella vulgaris, Ocimum basilicum, Salvia hispanica, Nepeta tenuifolia, Salvia rosmarinus), Fabaceae (Arachis hypogaea, Spatholobus suberectus), and Sapindaceae (Dimocarpus longan, Litchi chinensis) families were able to reduce the cytopathogenic effect (CPE) of SARS-CoV-2 in Vero E6 cells when the extracts were diluted to 16- to 960-fold (Fig. 6)
These compounds were categorized into five groups as viral protease inhibitors, guanine analog, inhibitors of SARS-CoV-2 function, ion channel modulators, and ionophoric antibiotics
Summary
We used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti–SARS-CoV-2 agents. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is an enveloped, positive-sense, single-stranded RNA coronavirus of the betacoronaviridae family [1], and the pathogen is responsible for the global pandemic that causes the coronavirusinduced disease in 2019 (COVID-19). Infection of SARS-CoV-2 starts with the interaction of trimeric viral spike (S) protein with human angiotensin-converting enzyme 2 (ACE2) receptor on airway epithelial cells, followed by viral entry and priming of human transmembrane protease serine 2 (TMPRSS2) that cleaves the S protein and initiates viral fusion (SI Appendix, Fig. S1) [3]. The viral proteins further undergo posttranslational modifications (such as glycosylation) at the endoplasmic reticulum (ER)-Golgi intermediate compartment, after which they are transported to the cell membrane for exocytosis [4]
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