Editorial

3 pages, 171 KiB

Open AccessEditorial

Broad-Spectrum Antivirals and Antiviral Combinations: An Editorial Update

by Denis Kainov and Valentyn Oksenych

Viruses 2022, 14(10), 2252; https://doi.org/10.3390/v14102252 - 14 Oct 2022

Cited by 2 | Viewed by 1461

Our Special Issue received a great deal of attention, and several important papers have recently been added to it [...] Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

2 pages, 177 KiB

Open AccessEditorial

Broad-Spectrum Antivirals and Antiviral Drug Combinations

by Valentyn Oksenych and Denis E. Kainov

Viruses 2022, 14(2), 301; https://doi.org/10.3390/v14020301 - 01 Feb 2022

Cited by 6 | Viewed by 2086

Abstract

Viral diseases consistently pose a substantial economic and public health burden worldwide [...] Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

Research

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10 pages, 2808 KiB

Open AccessCommunication

Antiviral Immunoglobulins of Chicken Egg Yolk for Potential Prevention of SARS-CoV-2 Infection

by Erlend Ravlo, Lasse Evensen, Gorm Sanson, Siri Hildonen, Aleksandr Ianevski, Per Olav Skjervold, Ping Ji, Wei Wang, Mari Kaarbø, Gerda Dominyka Kaynova, Denis E. Kainov and Magnar Bjørås

Viruses 2022, 14(10), 2121; https://doi.org/10.3390/v14102121 - 26 Sep 2022

Cited by 3 | Viewed by 2128

Abstract

Background: Some viruses cause outbreaks, which require immediate attention. Neutralizing antibodies could be developed for viral outbreak management. However, the development of monoclonal antibodies is often long, laborious, and unprofitable. Here, we report the development of chicken polyclonal neutralizing antibodies against SARS-CoV-2 infection. [...] Read more.

Background: Some viruses cause outbreaks, which require immediate attention. Neutralizing antibodies could be developed for viral outbreak management. However, the development of monoclonal antibodies is often long, laborious, and unprofitable. Here, we report the development of chicken polyclonal neutralizing antibodies against SARS-CoV-2 infection. Methods: Layers were immunized twice with 14-day intervals using the purified receptor-binding domain (RBD) of the S protein of SARS-CoV-2/Wuhan or SARS-CoV-2/Omicron. Eggs were harvested 14 days after the second immunization. Polyclonal IgY antibodies were extracted. Binding of anti-RBD IgYs was analyzed by immunoblot and indirect ELISA. Furthermore, the neutralization capacity of anti-RBD IgYs was measured in Vero-E6 cells infected with SARS-CoV-2-mCherry/Wuhan and SARS-CoV-2/Omicron using fluorescence and/or cell viability assays. In addition, the effect of IgYs on the expression of SARS-CoV-2 and host cytokine genes in the lungs of Syrian Golden hamsters was examined using qRT-PCR. Results: Anti-RBD IgYs efficiently bound viral RBDs in situ, neutralized the virus variants in vitro, and lowered viral RNA amplification, with minimal alteration of virus-mediated immune gene expression in vivo. Conclusions: Altogether, our results indicate that chicken polyclonal IgYs can be attractive targets for further pre-clinical and clinical development for the rapid management of outbreaks of emerging and re-emerging viruses. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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7 pages, 1505 KiB

Open AccessCommunication

Novel Synergistic Anti-Enteroviral Drug Combinations

by Aleksandr Ianevski, Eva Zusinaite, Tanel Tenson, Valentyn Oksenych, Wei Wang, Jan Egil Afset, Magnar Bjørås and Denis E. Kainov

Viruses 2022, 14(9), 1866; https://doi.org/10.3390/v14091866 - 25 Aug 2022

Cited by 6 | Viewed by 2272

Abstract

Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 [...] Read more.

Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. Results: We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir–vemurafenib, vemurafenib–pleconaril and rupintrivir–pleconaril combinations against EV1 infection. Conclusions: Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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13 pages, 2169 KiB

Open AccessArticle

Ivermectin Inhibits the Replication of Usutu Virus In Vitro

by Maria Elisabeth Wald, Claudia Claus, Andrea Konrath, Hermann Nieper, Aemero Muluneh, Volker Schmidt, Thomas Wilhelm Vahlenkamp and Michael Sieg

Viruses 2022, 14(8), 1641; https://doi.org/10.3390/v14081641 - 27 Jul 2022

Cited by 4 | Viewed by 1595

Abstract

Usutu virus (USUV) is an emerging mosquito-borne arbovirus within the genus Flavivirus, family Flaviviridae. Similar to the closely related West Nile virus (WNV), USUV infections are capable of causing mass mortality in wild and captive birds, especially blackbirds. In the last few [...] Read more.

Usutu virus (USUV) is an emerging mosquito-borne arbovirus within the genus Flavivirus, family Flaviviridae. Similar to the closely related West Nile virus (WNV), USUV infections are capable of causing mass mortality in wild and captive birds, especially blackbirds. In the last few years, a massive spread of USUV was present in the avian population of Germany and other European countries. To date, no specific antiviral therapies are available. Nine different approved drugs were tested for their antiviral effects on the replication of USUV in vitro in a screening assay. Ivermectin was identified as a potent inhibitor of USUV replication in three cell types from different species, such as simian Vero CCL-81, human A549 and avian TME R. A 2- to 7-log10 reduction of the viral titer in the supernatant was detected at a non-cytotoxic concentration of 5 µM ivermectin dependent on the applied cell line. IC₅₀ values of ivermectin against USUV lineage Africa 3 was found to be 0.55 µM in Vero CCL-81, 1.94 µM in A549 and 1.38 µM in TME-R cells. The antiviral efficacy was comparable between the USUV lineages Africa 2, Africa 3 and Europe 3. These findings show that ivermectin may be a candidate for further experimental and clinical studies addressing the treatment of USUV disease, especially in captive birds. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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14 pages, 1664 KiB

Open AccessArticle

Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses

by Sneha Munshi, Krishna Neupane, Sandaru M. Ileperuma, Matthew T. J. Halma, Jamie A. Kelly, Clarissa F. Halpern, Jonathan D. Dinman, Sarah Loerch and Michael T. Woodside

Viruses 2022, 14(2), 177; https://doi.org/10.3390/v14020177 - 18 Jan 2022

Cited by 19 | Viewed by 4765

Abstract

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal [...] Read more.

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates −1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of −1 PRF in SARS-CoV-2 also inhibited −1 PRF in a range of bat CoVs—the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on −1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed −1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit −1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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18 pages, 5208 KiB

Open AccessArticle

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

by Aleksandr Ianevski, Rouan Yao, Eva Zusinaite, Laura Sandra Lello, Sainan Wang, Eunji Jo, Jaewon Yang, Erlend Ravlo, Wei Wang, Hilde Lysvand, Kirsti Løseth, Valentyn Oksenych, Tanel Tenson, Marc P. Windisch, Minna M. Poranen, Anni I. Nieminen, Svein Arne Nordbø, Mona Høysæter Fenstad, Gunnveig Grødeland, Pål Aukrust, Marius Trøseid, Anu Kantele, Eglė Lastauskienė, Astra Vitkauskienė, Nicolas Legrand, Andres Merits, Magnar Bjørås and Denis E. Kainov Show full author list Hide full author list

Viruses 2021, 13(12), 2489; https://doi.org/10.3390/v13122489 - 11 Dec 2021

Cited by 20 | Viewed by 4207

Abstract

Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish [...] Read more.

Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFN

α

, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFN

α

–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 IFN

α

combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFN

α

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. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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14 pages, 6941 KiB

Open AccessArticle

Active Components of Commonly Prescribed Medicines Affect Influenza A Virus–Host Cell Interaction: A Pilot Study

by Aleksandr Ianevski, Rouan Yao, Eva Zusinaite, Hilde Lysvand, Valentyn Oksenych, Tanel Tenson, Magnar Bjørås and Denis Kainov

Viruses 2021, 13(8), 1537; https://doi.org/10.3390/v13081537 - 03 Aug 2021

Cited by 4 | Viewed by 11999

Abstract

Background: Every year, millions of people are hospitalized and thousands die from influenza A virus (FLUAV) infection. Most cases of hospitalizations and death occur among the elderly. Many of these elderly patients are reliant on medical treatment of underlying chronic diseases, such as [...] Read more.

Background: Every year, millions of people are hospitalized and thousands die from influenza A virus (FLUAV) infection. Most cases of hospitalizations and death occur among the elderly. Many of these elderly patients are reliant on medical treatment of underlying chronic diseases, such as arthritis, diabetes, and hypertension. We hypothesized that the commonly prescribed medicines for treatment of underlying chronic diseases can affect host responses to FLUAV infection and thus contribute to the morbidity and mortality associated with influenza. Therefore, the aim of this study was to examine whether commonly prescribed medicines could affect host responses to virus infection in vitro. Methods: We first identified 45 active compounds from a list of commonly prescribed medicines. Then, we constructed a drug–target interaction network and identified the potential implication of these interactions for FLUAV–host cell interplay. Finally, we tested the effect of 45 drugs on the viability, transcription, and metabolism of mock- and FLUAV-infected human retinal pigment epithelial (RPE) cells. Results: In silico drug–target interaction analysis revealed that drugs such as atorvastatin, candesartan, and hydroxocobalamin could target and modulate FLUAV–host cell interaction. In vitro experiments showed that at non-cytotoxic concentrations, these compounds affected the transcription and metabolism of FLUAV- and mock-infected cells. Conclusion: Many commonly prescribed drugs were found to modulate FLUAV–host cell interactions in silico and in vitro and could therefore affect their interplay in vivo, thus contributing to the morbidity and mortality of patients with influenza virus infections. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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Review

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21 pages, 2192 KiB

Open AccessReview

Immunoregulatory Intestinal Microbiota and COVID-19 in Patients with Type Two Diabetes: A Double-Edged Sword

by Pavlo Petakh, Iryna Kamyshna, Andriy Nykyforuk, Rouan Yao, John F. Imbery, Valentyn Oksenych, Mykhaylo Korda and Aleksandr Kamyshnyi

Viruses 2022, 14(3), 477; https://doi.org/10.3390/v14030477 - 25 Feb 2022

Cited by 19 | Viewed by 4403

Abstract

Coronavirus disease 2019, or COVID-19, is a major challenge facing scientists worldwide. Alongside the lungs, the system of organs comprising the GI tract is commonly targeted by COVID-19. The dysbiotic modulations in the intestine influence the disease severity, potentially due to the ability [...] Read more.

Coronavirus disease 2019, or COVID-19, is a major challenge facing scientists worldwide. Alongside the lungs, the system of organs comprising the GI tract is commonly targeted by COVID-19. The dysbiotic modulations in the intestine influence the disease severity, potentially due to the ability of the intestinal microbiota to modulate T lymphocyte functions, i.e., to suppress or activate T cell subpopulations. The interplay between the lungs and intestinal microbiota is named the gut–lung axis. One of the most usual comorbidities in COVID-19 patients is type 2 diabetes, which induces changes in intestinal microbiota, resulting in a pro-inflammatory immune response, and consequently, a more severe course of COVID-19. However, changes in the microbiota in this comorbid pathology remain unclear. Metformin is used as a medication to treat type 2 diabetes. The use of the type 2 diabetes drug metformin is a promising treatment for this comorbidity because, in addition to its hypoglycemic action, it can increase amount of intestinal bacteria that induce regulatory T cell response. This dual activity of metformin can reduce lung damage and improve the course of the COVID-19 disease. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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27 pages, 6730 KiB

Open AccessReview

Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review

by Abdul Wahaab, Bahar E Mustafa, Muddassar Hameed, Nigel J. Stevenson, Muhammad Naveed Anwar, Ke Liu, Jianchao Wei, Yafeng Qiu and Zhiyong Ma

Viruses 2022, 14(1), 44; https://doi.org/10.3390/v14010044 - 28 Dec 2021

Cited by 21 | Viewed by 3858

Abstract

Flaviviruses are known to cause a variety of diseases in humans in different parts of the world. There are very limited numbers of antivirals to combat flavivirus infection, and therefore new drug targets must be explored. The flavivirus NS2B-NS3 proteases are responsible for [...] Read more.

Flaviviruses are known to cause a variety of diseases in humans in different parts of the world. There are very limited numbers of antivirals to combat flavivirus infection, and therefore new drug targets must be explored. The flavivirus NS2B-NS3 proteases are responsible for the cleavage of the flavivirus polyprotein, which is necessary for productive viral infection and for causing clinical infections; therefore, they are a promising drug target for devising novel drugs against different flaviviruses. This review highlights the structural details of the NS2B-NS3 proteases of different flaviviruses, and also describes potential antiviral drugs that can interfere with the viral protease activity, as determined by various studies. Moreover, optimized in vitro reaction conditions for studying the NS2B-NS3 proteases of different flaviviruses may vary and have been incorporated in this review. The increasing availability of the in silico and crystallographic/structural details of flavivirus NS2B-NS3 proteases in free and drug-bound states can pave the path for the development of promising antiflavivirus drugs to be used in clinics. However, there is a paucity of information available on using animal cells and models for studying flavivirus NS2B-NS3 proteases, as well as on the testing of the antiviral drug efficacy against NS2B-NS3 proteases. Therefore, on the basis of recent studies, an effort has also been made to propose potential cellular and animal models for the study of flavivirus NS2B-NS3 proteases for the purposes of exploring flavivirus pathogenesis and for testing the efficacy of possible drugs targets, in vitro and in vivo. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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Other

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5 pages, 756 KiB

Open AccessComment

Nafamostat-Mediated Inhibition of SARS-CoV-2 Ribosomal Frameshifting Is Insufficient to Impair Viral Replication in Vero Cells. Comment on Munshi et al. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177

by Niklas Jäger, Markus Hoffmann, Stefan Pöhlmann and Nadine Krüger

Viruses 2022, 14(7), 1526; https://doi.org/10.3390/v14071526 - 13 Jul 2022

Cited by 3 | Viewed by 1566

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has been reported to have caused 18 [...] Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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8 pages, 989 KiB

Open AccessBrief Report

Nafamostat–Interferon-α Combination Suppresses SARS-CoV-2 Infection In Vitro and In Vivo by Cooperatively Targeting Host TMPRSS2

by Aleksandr Ianevski, Rouan Yao, Hilde Lysvand, Gunnveig Grødeland, Nicolas Legrand, Valentyn Oksenych, Eva Zusinaite, Tanel Tenson, Magnar Bjørås and Denis E. Kainov

Viruses 2021, 13(9), 1768; https://doi.org/10.3390/v13091768 - 04 Sep 2021

Cited by 15 | Viewed by 6407

Abstract

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in [...] Read more.

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world. Full article

(This article belongs to the Special Issue Broad Spectrum Antivirals and Antiviral Combinations)

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