Broad Anti-coronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo

Abstract

SARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with over 20 million recorded COVID-19 cases in August 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease. IMPORTANCE There are no FDA approved antivirals for any coronavirus, including SARS-CoV-2. Numerous drugs are already approved for human use that may have antiviral activity and therefore could potentially be rapidly re-purposed as antivirals. Here, we present data assessing the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV in vitro. We find 17 of these inhibit SARS-CoV-2, suggesting these may have pan-anti-coronaviral activity. We directly follow-up with seven of these and find they all inhibit infectious SARS-CoV-2 production. Moreover, we have evaluated chloroquine and chlorpromazine in vivo using mouse-adapted SARS-CoV. We find neither drug inhibited viral replication in the lungs, but both protected against clinical disease.

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

“…The in vitro activity of doxycycline against the SARS-CoV-2 (EC50 = 4.5 µM) was consistent with those reported with hydroxychloroquine [27,[29][30][31], with antimalarial drugs like chloroquine [27][28][29]32], amodiaquine [29,31,32], ferroquine [29], or mefloquine [29,31,33], antiviral agents like remdesivir [28,32,34] or lopinavir [32], and macrolides like azithromycin [34,35].…”

COVID-19: Analysis of Drug Repositioning Practice

“…The Vero cell line from kidney epithelial cells of an African green monkey [ 14 , 16 , 21 ] and its VeroE6 modification [ 12 , 15 , 17 , 18 , 20 – 22 ] were selected for testing in most studies. Human cell lines were used in three studies, i.e., Caco-2 (human colorectal adenocarcinoma cells) [ 19 ], Huh7 (hepatocellular carcinoma cells) [ 11 ], and HRCE (renal cortical epithelial cells) [ 13 ].…”

“…This allowed the activity of each compound to be analyzed in detail using one or several methods. The activities of the drugs were evaluated based on several experimental approaches, e.g., polymerase chain reaction with reverse transcription (RT-PCR) [11,14,15,20,22,23], determination of antiviral activity by evaluating inhibition of a cytopathic effect caused by the virus [16], determination of expression of viral nucleocapsid protein (N-protein) using immunofluorescence analysis [15,16,20,22], and counting the number of viable cells in culture by quantitative assay of the ATP concentration [12].…”

“…Ivermectin is used to treat parasitic infections and was selected for the study based on data for its activity against various RNA-viruses [14]. Sixty-eight drugs that were already demonstrated in previous studies to be active against SARS-CoV and MERS-CoV were evaluated for antiviral activity against SARS-CoV-2 [12,16]. A method for choosing tested drugs based on their inhibition of human coronavirus OC43 that causes seasonal URTI was reported.…”

In-Vitro Fluorescence Microscopy Studies Show Retention of Spike-Protein (SARS-Cov-2) on Cell Membrane in the Presence of Amodiaquin Dihydrochloride Dihydrate Drug

“…However, mechanism of action is still unknown. The ADD second test drug, an FDA-approved drug for anti-malarial, anti-Ebola activity [14] [15], is also in the list of re-purposed drug that could inhibit SARS-Cov-2 [16]. The third drug Remidesivir, an established antiviral drug could also inhibit SARS-CoV-2 viral titre compared to control [13].…”