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Viruses
Special Issues
Towards Host-Centric Antivirals
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Towards Host-Centric Antivirals

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 10377

Special Issue Editors

Prof. Dr. Kin-Chow Chang

E-Mail Website
Guest Editor
School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
Interests: host-centric antivirals; influenza A virus; coronavirus, SARS-CoV-2; respiratory syncytial virus; innate immunity; virus–host interactions; host resistance to viral infection
Dr. Leah Goulding

E-Mail
Guest Editor
African Swine Fever Virus, The Pirbright Institute, Pirbright, UK
Interests: antiviral; influenza A virus; African swine fever virus; innate immunity; virus–host interactions; host-centric antivirals; antiviral resistance; drug repurposing

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to promote the research and development of host-based antivirals as an alternative approach to virus-based antiviral targeting.

Ninety antiviral drugs have been approved for the treatment of only nine human diseases, highlighting the challenges of antiviral development. Targeting viral proteins through direct-acting antivirals has been, and remains, the primary strategy employed. However, the emergence of antiviral resistance is a significant challenge, particularly for highly mutable RNA viruses such as influenza A viruses. An alternative strategy is to exploit the absolute dependency of viruses on host cells for their replication by targeting host processes or factors, either inhibiting pro-viral host factors or inducing antiviral host-innate immune responses. A further advantage of this strategy is its potential broad-spectrum antiviral activity against related (RNA) viruses. The development of broad-spectrum antivirals which can be used to treat emergent viruses is clearly advantageous, as exemplified by the current pandemic. Even in the presence of effective vaccines, antivirals for treatment and prophylaxis are essential in managing active viral infections. Furthermore, understanding the mechanism of action of particular host-centric antivirals could further refine our understanding of host–virus interactions.

We invite all researchers working in the field of antiviral development to submit original research papers, short communications or reviews to this Special Issue of Viruses to highlight recent advances and further the discussion on host-centric therapeutics.

Prof. Dr. Kin-Chow Chang
Dr. Leah Goulding
Guest Editors

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. Viruses 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 2600 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

  • antiviral
  • host-centric
  • broad-spectrum
  • therapeutics
  • virus–host interactions

Published Papers (2 papers)

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Research

18 pages, 2566 KiB  
Article
Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells
by Carolina Q. Sacramento, Natalia Fintelman-Rodrigues, Suelen S. G. Dias, Jairo R. Temerozo, Aline de Paula D. Da Silva, Carine S. da Silva, Camilla Blanco, André C. Ferreira, Mayara Mattos, Vinicius C. Soares, Filipe Pereira-Dutra, Milene Dias Miranda, Debora F. Barreto-Vieira, Marcos Alexandre N. da Silva, Suzana S. Santos, Mateo Torres, Otávio Augusto Chaves, Rajith K. R. Rajoli, Alberto Paccanaro, Andrew Owen, Dumith Chequer Bou-Habib, Patrícia T. Bozza and Thiago Moreno L. Souzaadd Show full author list remove Hide full author list
Viruses 2022, 14(2), 374; https://doi.org/10.3390/v14020374 - 11 Feb 2022
Cited by 10 | Viewed by 2705
Abstract
Despite the development of specific therapies against severe acute respiratory coronavirus 2 (SARS-CoV-2), the continuous investigation of the mechanism of action of clinically approved drugs could provide new information on the druggable steps of virus–host interaction. For example, chloroquine (CQ)/hydroxychloroquine (HCQ) lacks in [...] Read more.
Despite the development of specific therapies against severe acute respiratory coronavirus 2 (SARS-CoV-2), the continuous investigation of the mechanism of action of clinically approved drugs could provide new information on the druggable steps of virus–host interaction. For example, chloroquine (CQ)/hydroxychloroquine (HCQ) lacks in vitro activity against SARS-CoV-2 in TMPRSS2-expressing cells, such as human pneumocyte cell line Calu-3, and likewise, failed to show clinical benefit in the Solidarity and Recovery clinical trials. Another antimalarial drug, mefloquine, which is not a 4-aminoquinoline like CQ/HCQ, has emerged as a potential anti-SARS-CoV-2 antiviral in vitro and has also been previously repurposed for respiratory diseases. Here, we investigated the anti-SARS-CoV-2 mechanism of action of mefloquine in cells relevant for the physiopathology of COVID-19, such as Calu-3 cells (that recapitulate type II pneumocytes) and monocytes. Molecular pathways modulated by mefloquine were assessed by differential expression analysis, and confirmed by biological assays. A PBPK model was developed to assess mefloquine’s optimal doses for achieving therapeutic concentrations. Mefloquine inhibited SARS-CoV-2 replication in Calu-3, with an EC50 of 1.2 µM and EC90 of 5.3 µM. It reduced SARS-CoV-2 RNA levels in monocytes and prevented virus-induced enhancement of IL-6 and TNF-α. Mefloquine reduced SARS-CoV-2 entry and synergized with Remdesivir. Mefloquine’s pharmacological parameters are consistent with its plasma exposure in humans and its tissue-to-plasma predicted coefficient points suggesting that mefloquine may accumulate in the lungs. Altogether, our data indicate that mefloquine’s chemical structure could represent an orally available host-acting agent to inhibit virus entry. Full article
(This article belongs to the Special Issue Towards Host-Centric Antivirals)
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18 pages, 35740 KiB  
Article
Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
by Valeria Inés Segatori, Juan Garona, Lorena Grisel Caligiuri, Juan Bizzotto, Rosario Lavignolle, Ayelén Toro, Pablo Sanchis, Eduardo Spitzer, Alejandro Krolewiecki, Geraldine Gueron and Daniel Fernando Alonso
Viruses 2021, 13(10), 2084; https://doi.org/10.3390/v13102084 - 15 Oct 2021
Cited by 7 | Viewed by 6814
Abstract
Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho [...] Read more.
Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations. Full article
(This article belongs to the Special Issue Towards Host-Centric Antivirals)
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