Synergistic and Antagonistic Drug Combinations against SARS-CoV-2

Bobrowski, Tesia; Chen, Lu; Eastman, Richard T.; Itkin, Zina; Shinn, Paul; Chen, Catherine Z.; Guo, Hui; Zheng, Wei; Michael, Sam; Simeonov, Anton; Hall, Matthew D.; Zakharov, Alexey; Muratov, Eugene

doi:10.1016/j.ymthe.2020.12.016

Cited by 92 publications

(87 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we understand that NTZ is a safe drug, the dosages investigated here were relatively modest and were based on previous studies that explored the antiviral effect for influenza viruses using 600 mg BID [28] . Of note, NTZ has been previously employed at 1000 mg BID without significant safety concerns [ 29 , 31 , 32 , 37 ]. Also, previous dose estimates have indicated that higher doses will be required to achieve SARS-COV-2 suppressive concentrations at Concentration trough levels [38] .…”

Section: Discussionmentioning

confidence: 99%

Nitazoxanide superiority to placebo to treat moderate COVID-19 – A Pilot prove of concept randomized double-blind clinical trial.

Blum¹,

Cimerman²,

Hunter³

et al. 2021

eClinicalMedicine

View full text Add to dashboard Cite

Background The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates’ drugs. Nitazoxanide (NTZ) has a broad antiviral effect. Methods This was a randomized, double-blind pilot clinical trial comparing NTZ 600 mg BID versus Placebo for seven days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency from May 20 th , 2020, to September 21 st , 2020 (ClinicalTrials.gov NCT04348409). Clinical and virologic endpoints and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used. Findings Two patients died in the NTZ arm compared to 6 in the placebo arm ( p = 0.564). NTZ was superior to placebo when considering SSD ( p < 0001), the mean time for hospital discharge (6.6 vs. 14 days, p = 0.021), and negative PCR at day 21 ( p = 0.035), whereas the placebo group presented more adverse events ( p = 0.04). Among adverse events likely related to the study drug, 14 were detected in the NTZ group and 22 in placebo ( p = 0.24). Among the 30 adverse events unlikely related, 21 occurred in the placebo group ( p = 0.04). A decrease from baseline was higher in the NTZ group for d -Dimer ( p = 0.001), US-RCP ( p < 0.002), TNF ( p < 0.038), IL-6 ( p < 0.001), IL-8 ( p = 0.014), HLA DR. on CD4 + T lymphocytes ( p < 0.05), CD38 in CD4 + and CD8 + T (both p < 0.05), and CD38 and HLA-DR. on CD4+ ( p < 0.01) Interpretation Compared to placebo in clinical and virologic outcomes and improvement of inflammatory outcomes, the superiority of NTZ warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms.

show abstract

Section: Discussionmentioning

confidence: 99%

Nitazoxanide superiority to placebo to treat moderate COVID-19 – A Pilot prove of concept randomized double-blind clinical trial.

Blum¹,

Cimerman²,

Hunter³

et al. 2021

eClinicalMedicine

View full text Add to dashboard Cite

show abstract

“…Compared with wild-type virus, reporter virus assays typically have a higher dynamic range and potentially higher throughput capacity. High-throughput assay formats also enable the screening and assessment of antiviral combinations in cell culture, which require a large number of experimental conditions to be evaluated [ 73 ].…”

Section: Preclinical Toolsmentioning

confidence: 99%

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Hall

Anderson

et al. 2021

The Journal of Infectious Diseases

View full text Add to dashboard Cite

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on November 6, 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for COVID-19, including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss SARS-CoV-2 targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.

show abstract

“…Because the SARS-CoV-2 entry and infection of cells comprises multiple critical biological processes inside infected cells, we further evaluated the potential of the combination of targeting ChoMCyto genes and other processes such as viral replication in COVID-19 treatment. To do so, we elicited a recent combination screening study from The National Center for Advancing Translational Sciences (NCATS) [ 19 , 20 ], where 15 host-targeting compounds were combined with at least one of 11 antivirals [nine known antivirals, two potent SARS-CoV-2 candidates nitazoxanide and hydroxychloroquine (HCQ)] ( Figure 3A , Supplementary Data 11 ). For each host-targeting compound in the columns of Figure 3A , we summarized its synergistic effect with the 11 antivirals (see Methods, Row ‘Synergism’ in Figure 3A ) as well as the ChoMCyto score (the middle row in Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

“…Bobrowski et al . [ 20 ] measured the anti-SARS-CoV-2 synergism of 73 drug combinations in vitro . As they calculated synergistic (HSA.…”

Section: Methodsmentioning

confidence: 99%

Published anti-SARS-CoV-2 in vitro hits share common mechanisms of action that synergize with antivirals

Xing

Paithankar

Liu

et al. 2021

Briefings in Bioinformatics

View full text Add to dashboard Cite

The global efforts in the past year have led to the discovery of nearly 200 drug repurposing candidates for COVID-19. Gaining more insights into their mechanisms of action could facilitate a better understanding of infection and the development of therapeutics. Leveraging large-scale drug-induced gene expression profiles, we found 36% of the active compounds regulate genes related to cholesterol homeostasis and microtubule cytoskeleton organization. Following bioinformatics analyses revealed that the expression of these genes is associated with COVID-19 patient severity and has predictive power on anti-SARS-CoV-2 efficacy in vitro. Monensin, a top new compound that regulates these genes, was further confirmed as an inhibitor of SARS-CoV-2 replication in Vero-E6 cells. Interestingly, drugs co-targeting cholesterol homeostasis and microtubule cytoskeleton organization processes more likely present a synergistic effect with antivirals. Therefore, potential therapeutics could be centered around combinations of targeting these processes and viral proteins.

show abstract

Synergistic and Antagonistic Drug Combinations against SARS-CoV-2

Cited by 92 publications

References 49 publications

Nitazoxanide superiority to placebo to treat moderate COVID-19 – A Pilot prove of concept randomized double-blind clinical trial.

Nitazoxanide superiority to placebo to treat moderate COVID-19 – A Pilot prove of concept randomized double-blind clinical trial.

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Published anti-SARS-CoV-2 in vitro hits share common mechanisms of action that synergize with antivirals

Contact Info

Product

Resources

About