Combination Treatment With Remdesivir and Ivermectin Exerts Highly Synergistic and Potent Antiviral Activity Against Murine Coronavirus Infection

DOI record: { "DOI": "10.3389/fcimb.2021.700502", "ISSN": [ "2235-2988" ], "URL": "http://dx.doi.org/10.3389/fcimb.2021.700502", "abstract": "<jats:p>The recent COVID-19 pandemic has highlighted the urgency to develop effective antiviral therapies against the disease. Murine hepatitis virus (MHV) is a coronavirus that infects mice and shares some sequence identity to SARS-CoV-2. Both viruses belong to the <jats:italic>Betacoronavirus </jats:italic>genus, and MHV thus serves as a useful and safe surrogate model for SARS-CoV-2 infections. Clinical trials have indicated that remdesivir is a potentially promising antiviral drug against COVID-19. Using an<jats:italic>in vitro</jats:italic>model of MHV infection of RAW264.7 macrophages, the safety and efficacy of monotherapy of remdesivir, chloroquine, ivermectin, and doxycycline were investigated. Of the four drugs tested, remdesivir monotherapy exerted the strongest inhibition of live virus and viral RNA replication of about 2-log<jats:sub>10</jats:sub>and 1-log<jats:sub>10</jats:sub>, respectively (at 6 µM). Ivermectin treatment showed the highest selectivity index. Combination drug therapy was also evaluated using remdesivir (6 µM) together with chloroquine (15 µM), ivermectin (2 µM) or doxycycline (15 µM) – above their IC50 values and at high macrophage cell viability of over 95%. The combination of remdesivir and ivermectin exhibited highly potent synergism by achieving significant reductions of about 7-log<jats:sub>10</jats:sub>of live virus and 2.5-log<jats:sub>10</jats:sub>of viral RNA in infected macrophages. This combination also resulted in the lowest cytokine levels of IL-6, TNF-α, and leukemia inhibitory factor. The next best synergistic combination was remdesivir with doxycycline, which decreased levels of live virus by ~3-log<jats:sub>10</jats:sub>and viral RNA by ~1.5-log<jats:sub>10</jats:sub>. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future<jats:italic>in vivo</jats:italic>experiments and clinical trials for the treatment of SARS-CoV-2 infection.</jats:p>", "alternative-id": [ "10.3389/fcimb.2021.700502" ], "author": [ { "affiliation": [], "family": "Tan", "given": "Yu Ling", "sequence": "first" }, { "affiliation": [], "family": "Tan", "given": "Kevin S. W.", "sequence": "additional" }, { "affiliation": [], "family": "Chu", "given": "Justin Jang Hann", "sequence": "additional" }, { "affiliation": [], "family": "Chow", "given": "Vincent T.", "sequence": "additional" } ], "container-title": "Frontiers in Cellular and Infection Microbiology", "container-title-short": "Front. Cell. Infect. Microbiol.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2021, 7, 30 ] ], "date-time": "2021-07-30T16:51:27Z", "timestamp": 1627663887000 }, "deposited": { "date-parts": [ [ 2023, 1, 5 ] ], "date-time": "2023-01-05T23:31:03Z", "timestamp": 1672961463000 }, "indexed": { "date-parts": [ [ 2024, 9, 12 ] ], "date-time": "2024-09-12T18:33:08Z", "timestamp": 1726165988944 }, "is-referenced-by-count": 22, "issued": { "date-parts": [ [ 2021, 7, 30 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 7, 30 ] ], "date-time": "2021-07-30T00:00:00Z", "timestamp": 1627603200000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fcimb.2021.700502/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2021, 7, 30 ] ] }, "published-online": { "date-parts": [ [ 2021, 7, 30 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "DOI": "10.1164/ajrccm.161.4.9907147", "article-title": "Multiple Combination Bactericidal Antibiotic Testing for Patients With Cystic Fibrosis Infected With Burkholderia Cepacia", "author": "Aaron", "doi-asserted-by": "publisher", "first-page": "1206", "journal-title": "Am. 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