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Microorganisms
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Antiviral Research
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Antiviral Research

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 23774

Special Issue Editor

Dr. Valeria Cagno

E-Mail Website
Guest Editor
Department of Microbiology and Molecular Medicine, University of Geneva Medical School, 1205 Geneva, Switzerland
Interests: broad-spectrum antivirals; human airway epithelia; SARS-CoV2; respiratory viruses; Zika virus; Herpes Simplex Virus

Special Issue Information

Dear Colleagues,

Despite the great successes in identifying antivirals for life-threatening pathogens such as HIV and hepatitis C virus, we lack antivirals for the majority of other viruses. This is worrisome, particularly during a pandemic. COVID-19 highlighted, once more, that we are not able, when a new virus emerges, to develop specific antivirals in a short time. Therefore, research in this field is extremely important, independently of pandemics and immediate market revenues. Broad-spectrum antivirals, such as pan-coronavirus or pan-flavivirus, would be extremely useful for current and future epidemics.

Major challenges in the identification of antivirals rely on the models used to screen the molecules. Immortalized cell lines, laboratory-adapted viruses, and genetically engineered mouse models are widely used but have several limitations. In recent years, the use of organoids, human airway epithelial cell cultures, organ-on-chip, and viral clinical isolates improved significantly the identification of antivirals. Another limitation in the field is the long path of clinical trials, which can be partly overcome through drug repurposing. High throughput screening of large chemical libraries is now widely used and allows the rapid identification of promising molecules.

This Special Issue of Microorganisms will be dedicated to the following themes: identification of new antiviral molecules both from natural and synthetic origin, preclinical studies of antivirals previously identified, repurposing of drugs as antivirals, challenges and tools for antiviral discovery, reviews of antivirals available for a specific viral pathogen or reviews of a specific class of antivirals (i.e., nucleoside analogues, immunomodulatory molecules, fusion inhibitors)

Dr. Valeria Cagno
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • SARS-CoV2
  • Screening
  • Drug repurposing
  • Organoids
  • Nucleoside analogues
  • Entry inhibitor Preclinical study
  • Broad-spectrum antiviral

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Published Papers (6 papers)

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Research

Jump to: Review

19 pages, 2231 KiB  
Article
Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
by Salvatore Ferla, Carmine Varricchio, William Knight, Pui Kei Ho, Fabiana Saporito, Beatrice Tropea, Giulio Fagan, Ben Matthew Flude, Federica Bevilacqua, Nanci Santos-Ferreira, Jana Van Dycke, Johan Neyts, Andrea Brancale, Joana Rocha-Pereira and Marcella Bassetto
Microorganisms 2021, 9(9), 1795; https://doi.org/10.3390/microorganisms9091795 - 24 Aug 2021
Cited by 2 | Viewed by 3848
Abstract
Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines [...] Read more.
Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents. Full article
(This article belongs to the Special Issue Antiviral Research)
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16 pages, 2087 KiB  
Article
The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses
by Arianna Calistri, Anna Luganini, Barbara Mognetti, Elizabeth Elder, Giulia Sibille, Valeria Conciatori, Claudia Del Vecchio, Stefano Sainas, Donatella Boschi, Nuria Montserrat, Ali Mirazimi, Marco Lucio Lolli, Giorgio Gribaudo and Cristina Parolin
Microorganisms 2021, 9(8), 1731; https://doi.org/10.3390/microorganisms9081731 - 14 Aug 2021
Cited by 23 | Viewed by 4012
Abstract
Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an [...] Read more.
Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats. Full article
(This article belongs to the Special Issue Antiviral Research)
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9 pages, 764 KiB  
Communication
Antiviral Efficacy of Ribavirin and Favipiravir against Hantaan Virus
by Jennifer Mayor, Olivier Engler and Sylvia Rothenberger
Microorganisms 2021, 9(6), 1306; https://doi.org/10.3390/microorganisms9061306 - 15 Jun 2021
Cited by 16 | Viewed by 3011
Abstract
Ecological changes, population movements and increasing urbanization promote the expansion of hantaviruses, placing humans at high risk of virus transmission and consequent diseases. The currently limited therapeutic options make the development of antiviral strategies an urgent need. Ribavirin is the only antiviral used [...] Read more.
Ecological changes, population movements and increasing urbanization promote the expansion of hantaviruses, placing humans at high risk of virus transmission and consequent diseases. The currently limited therapeutic options make the development of antiviral strategies an urgent need. Ribavirin is the only antiviral used currently to treat hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV), even though severe side effects are associated with this drug. We therefore investigated the antiviral activity of favipiravir, a new antiviral agent against RNA viruses. Both ribavirin and favipiravir demonstrated similar potent antiviral activity on HTNV infection. When combined, the efficacy of ribavirin is enhanced through the addition of low dose favipiravir, highlighting the possibility to provide better treatment than is currently available. Full article
(This article belongs to the Special Issue Antiviral Research)
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18 pages, 2228 KiB  
Article
Interferon Lambda Delays the Emergence of Influenza Virus Resistance to Oseltamivir
by Chiara Medaglia, Arnaud Charles-Antoine Zwygart, Paulo Jacob Silva, Samuel Constant, Song Huang, Francesco Stellacci and Caroline Tapparel
Microorganisms 2021, 9(6), 1196; https://doi.org/10.3390/microorganisms9061196 - 1 Jun 2021
Cited by 8 | Viewed by 3375
Abstract
Influenza viruses are a leading cause of morbidity and mortality worldwide. These air-borne pathogens are able to cross the species barrier, leading to regular seasonal epidemics and sporadic pandemics. Influenza viruses also possess a high genetic variability, which allows for the acquisition of [...] Read more.
Influenza viruses are a leading cause of morbidity and mortality worldwide. These air-borne pathogens are able to cross the species barrier, leading to regular seasonal epidemics and sporadic pandemics. Influenza viruses also possess a high genetic variability, which allows for the acquisition of resistance mutations to antivirals. Combination therapies with two or more drugs targeting different mechanisms of viral replication have been considered an advantageous option to not only enhance the effectiveness of the individual treatments, but also reduce the likelihood of resistance emergence. Using an in vitro infection model, we assessed the barrier to viral resistance of a combination therapy with the neuraminidase inhibitor oseltamivir and human interferon lambda against the pandemic H1N1 A/Netherlands/602/2009 (H1N1pdm09) virus. We serially passaged the virus in a cell line derived from human bronchial epithelial cells in the presence or absence of increasing concentrations of oseltamivir alone or oseltamivir plus interferon lambda. While the treatment with oseltamivir alone quickly induced the emergence of antiviral resistance through a single mutation in the neuraminidase gene, the co-administration of interferon lambda delayed the emergence of drug-resistant influenza virus variants. Our results suggest a possible clinical application of interferon lambda in combination with oseltamivir to treat influenza. Full article
(This article belongs to the Special Issue Antiviral Research)
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Review

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21 pages, 846 KiB  
Review
Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections
by Nanci Santos-Ferreira, Jana Van Dycke, Johan Neyts and Joana Rocha-Pereira
Microorganisms 2021, 9(8), 1599; https://doi.org/10.3390/microorganisms9081599 - 27 Jul 2021
Cited by 16 | Viewed by 4453
Abstract
Acute gastroenteritis caused by virus has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The main culprits are rotaviruses, noroviruses, sapoviruses, astroviruses, and enteric adenoviruses. Currently, there are no antiviral drugs available for the prevention or [...] Read more.
Acute gastroenteritis caused by virus has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The main culprits are rotaviruses, noroviruses, sapoviruses, astroviruses, and enteric adenoviruses. Currently, there are no antiviral drugs available for the prevention or treatment of viral gastroenteritis. Here, we describe the antivirals that were identified as having in vitro and/or in vivo activity against these viruses, originating from in silico design or library screening, natural sources or being repurposed drugs. We also highlight recent advances in model systems available for this (hard to cultivate) group of viruses, such as organoid technologies, and that will facilitate antiviral studies as well as fill some of current knowledge gaps that hamper the development of highly efficient therapies against gastroenteric viruses. Full article
(This article belongs to the Special Issue Antiviral Research)
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14 pages, 545 KiB  
Review
Viruses Like Sugars: How to Assess Glycan Involvement in Viral Attachment
by Gregory Mathez and Valeria Cagno
Microorganisms 2021, 9(6), 1238; https://doi.org/10.3390/microorganisms9061238 - 7 Jun 2021
Cited by 8 | Viewed by 3700
Abstract
The first step of viral infection requires interaction with the host cell. Before finding the specific receptor that triggers entry, the majority of viruses interact with the glycocalyx. Identifying the carbohydrates that are specifically recognized by different viruses is important both for assessing [...] Read more.
The first step of viral infection requires interaction with the host cell. Before finding the specific receptor that triggers entry, the majority of viruses interact with the glycocalyx. Identifying the carbohydrates that are specifically recognized by different viruses is important both for assessing the cellular tropism and for identifying new antiviral targets. Advances in the tools available for studying glycan–protein interactions have made it possible to identify them more rapidly; however, it is important to recognize the limitations of these methods in order to draw relevant conclusions. Here, we review different techniques: genetic screening, glycan arrays, enzymatic and pharmacological approaches, and surface plasmon resonance. We then detail the glycan interactions of enterovirus D68 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlighting the aspects that need further clarification. Full article
(This article belongs to the Special Issue Antiviral Research)
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