Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro

Abstract

<jats:title>Abstract</jats:title><jats:p>COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Using <jats:italic>in silico</jats:italic> approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them <jats:italic>in vitro</jats:italic>. Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections.</jats:p>

GNS561 exhibits potentin vitroantiviral activity against SARS-CoV-2 through autophagy inhibition

“…It was also reported that remdesivir and HCQ exhibited a strong antagonism (28). Here, we showed that a combination of the replication inhibitor, remdesivir with the autophagy inhibitor, GNS561 demonstrated strong synergy in vitro, supporting future clinical evaluation of such combination regimens.…”

“…Thus, there is some interest in using drug combinations against SARS-CoV-2. Interestingly, it was recently reported that nitazoxanide in combination with amodiaquine, umifenovir or remdesivir presented a significant synergy against SARS-CoV-2 (28).…”

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19

“…The study reported high synergy of nitazoxanide with three antivirals remdesivir, amodiaquine and umifenovir. The study also reports that the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism ( Bobrowski et al, 2020 ). The combination use of nitazoxanide with macrolide antibiotic azithromycin ( Kelleni, 2020 ) and antimalarial drug hydroxychloroquine has been proposed ( Padmanabhan, 2020 ).…”

“…A significant finding is the ability of nitazoxanide to promote balance between pro-inflammatory and anti-inflammatory responses in humans, which could play a crucial role in COVID-19 by curbing the hyperinflammatory cytokine storm ( Jasenosky et al, 2019 ; Martins-Filho et al, 2020 ; Rossignol, 2016 ; Shakya et al, 2018a ). Repurposing nitazoxanide against COVID-19 has been suggested in many reports ( Alonso and Farina, 2020 ; Arshad et al, 2020 ; Bobrowski et al, 2020 ; Chibber et al, 2020 ; Mahmoud et al, 2020 ; Martins-Filho et al, 2020 ; Padmanabhan, 2020 ; Padmanabhan and Padmanabhan, 2020 ; Pepperrell et al, 2020 ; Rajoli et al, 2020 ). The approval of a number of clinical trials with nitazoxanide further substantiates this hypothesis ( https://clinicaltrials.gov/ ) (Nitazoxanide clinical trials, 2020).…”

The COVID-19 PHARMACOME: A method for the rational selection of drug repurposing candidates from multimodal knowledge harmonization

“…As described in Ellinger et al, 36 In addition, recently published data from the work of Bobrowski et al 37 , were mapped to the COVID-19 supergraph and compared to the results of the combinatorial treatment experiments performed here.…”