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

Abstract

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 Betacoronavirus 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 in vitro 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-log10 and 1-log10, 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-log10 of live virus and 2.5-log10 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-log10 and viral RNA by ~1.5-log10. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future in vivo experiments and clinical trials for the treatment of SARS-CoV-2 infection.

Mapping Scientific Productivity Trends and Hotspots in Remdesivir Research Publications: A Bibliometric Study from 2016 to 2021

“…Furthermore, the combination of remdesivir with doxycycline reduces virus levels. The authors suggested further studies based on their findings to explore the mechanisms of action of combination therapy, in vivo experiments, and clinical trials in the treatment of SARS-CoV-2 infection [ 70 ]. Baricitinib, in combination with remdesivir, has been reported to be superior to the monotherapeutic use of remdesivir to reduce recovery times and accelerate clinical-status improvement for COVID-19 patients [ 71 ], particularly among those receiving high-flow oxygen or noninvasive ventilation.…”

Bioassay-Guided Fractionation of Erythrostemon yucatanensis (Greenm.) Gagnon & GP Lewis Components with Anti-hemagglutinin Binding Activity against Influenza A/H1N1 Virus

“…An individual evaluation of the pure standards of these sterols did not show any antiviral activity, suggesting that the HA inhibitory activity resulted from a synergistic effect among these compounds. The identification of molecules of plant origin and, in particular, the synergistic effect of these molecules should be investigated deeply, as the greater efficiency of combinations of molecules with antiviral effects has been previously reported [ 31 , 32 ]. The most important plant sterols (commonly known as phytosterols) are stigmasterol, campesterol and β-sitosterol [ 33 ].…”

Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2

“…This suggested that a drug combination strategy would help improve antiviral activity. Additionally, the combination of Remdesivir and Ivermectin showed synergism 49,50 . As both Remdesivir and Favipiravir target viral RdRp, their interaction with Ivermectin may represent a similar synergistic mechanism.…”