Dataset Information

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections.

ABSTRACT: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

SUBMITTER: Ianevski A

PROVIDER: S-EPMC8705725 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections.

Ianevski Aleksandr A Yao Rouan R Zusinaite Eva E Lello Laura Sandra LS Wang Sainan S Jo Eunji E Yang Jaewon J Ravlo Erlend E Wang Wei W Lysvand Hilde H Løseth Kirsti K Oksenych Valentyn V Tenson Tanel T Windisch Marc P MP Poranen Minna M MM Nieminen Anni I AI Nordbø Svein Arne SA Fenstad Mona Høysæter MH Grødeland Gunnveig G Aukrust Pål P Trøseid Marius M Kantele Anu A Lastauskienė Eglė E Vitkauskienė Astra A Legrand Nicolas N Merits Andres A Bjørås Magnar M Kainov Denis E DE

Viruses 20211211 12

<h4>Background</h4>There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects.<h4>Methods</h4>Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro.<h4>Results</h4>While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be ...[more]

PMID: 34960758

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Project description:Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.

Project description:Background: Testing of possibly infected individuals remains cornerstone of containing the spread of SARS-CoV-2. Detection dogs could contribute to mass screening. Previous research demonstrated canines' ability to detect SARS-CoV-2-infections but has not investigated if dogs can differentiate between COVID-19 and other virus infections. Methods: Twelve dogs were trained to detect SARS-CoV-2 positive samples. Three test scenarios were performed to evaluate their ability to discriminate SARS-CoV-2-infections from viral infections of a different aetiology. Naso- and oropharyngeal swab samples from individuals and samples from cell culture both infected with one of 15 viruses that may cause COVID-19-like symptoms were presented as distractors in a randomised, double-blind study. Dogs were either trained with SARS-CoV-2 positive saliva samples (test scenario I and II) or with supernatant from cell cultures (test scenario III). Results: When using swab samples from individuals infected with viruses other than SARS-CoV-2 as distractors (test scenario I), dogs detected swab samples from SARS-CoV-2-infected individuals with a mean diagnostic sensitivity of 73.8% (95% CI: 66.0-81.7%) and a specificity of 95.1% (95% CI: 92.6-97.7%). In test scenario II and III cell culture supernatant from cells infected with SARS-CoV-2, cells infected with other coronaviruses and non-infected cells were presented. Dogs achieved mean diagnostic sensitivities of 61.2% (95% CI: 50.7-71.6%, test scenario II) and 75.8% (95% CI: 53.0-98.5%, test scenario III), respectively. The diagnostic specificities were 90.9% (95% CI: 87.3-94.6%, test scenario II) and 90.2% (95% CI: 81.1-99.4%, test scenario III), respectively. Conclusion: In all three test scenarios the mean specificities were above 90% which indicates that dogs can distinguish SARS-CoV-2-infections from other viral infections. However, compared to earlier studies our scent dogs achieved lower diagnostic sensitivities. To deploy COVID-19 detection dogs as a reliable screening method it is therefore mandatory to include a variety of samples from different viral respiratory tract infections in dog training to ensure a successful discrimination process.

Dataset Information

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections.

Publications

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections.

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