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Viruses
Special Issues
Host Targeted Therapeutics against Virus Infections
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Host Targeted Therapeutics against Virus Infections

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 December 2022) | Viewed by 20023

Special Issue Editors

Prof. Dr. Oliver Planz

E-Mail Website
Guest Editor
Institute of Cell Biology and Immunology, Eberhard Karls University, 72076 Tuebingen, Germany
Interests: immunology of viral infections; host cell targeted antivirals; virus cell interaction
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Stephan Ludwig

E-Mail Website
Guest Editor
Institute of Virology, University of Münster, 48149 Münster, Germany
Interests: interaction of influenza viruses and other respiratory pathogens with the host cells and immune system; innate immune mechanisms in acute virus infections; host-targeted antivirals against respiratory viruses
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Stephan Pleschka

E-Mail Website
Guest Editor
Justus Liebig University, Giessen, Germany
Interests: molecular biology/genetics of IV; viral factors allowing host infection; cellular functions essential for IV replication
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The current Covid-19 pandemic and the frequent emergence and re-emergence of novel viruses highlights the urgent need for effective antivirals. The fact that every virus needs host cells to replicate sparked increasing interest in host-directed drugs that act as antivirals (host-targeted antivirals, HTA). While this approach had been heavily debated 20 years ago, the idea to target host functions for antiviral therapy was boosted due to technical developments such as cell-omics approaches and has now become widely accepted. (inhibitors of cell signaling pathways have received special attention in this respect). In this Special Issue, we want to summarize the latest findings in this field and would like to encourage research groups working on host-targeted antivirals to submit their latest findings.

Prof. Dr. Oliver Planz
Prof. Dr. Stephan Ludwig
Prof. Dr. Stephan Pleschka
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

  • influenza
  • COVID-19
  • host targeting antivirals
  • inhibitors of post translational modification and maturation of viral proteins
  • inhibitors of viral entry and intra-cellular transport

Published Papers (7 papers)

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Research

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22 pages, 3784 KiB  
Article
The Interplay among Glucocorticoid Therapy, Platelet-Activating Factor and Endocannabinoid Release Influences the Inflammatory Response to COVID-19
by Jonatan C. S. de Carvalho, Pedro V. da Silva-Neto, Diana M. Toro, Carlos A. Fuzo, Viviani Nardini, Vinícius E. Pimentel, Malena M. Pérez, Thais F. C. Fraga-Silva, Camilla N. S. Oliveira, Augusto M. Degiovani, Fátima M. Ostini, Marley R. Feitosa, Rogerio S. Parra, José J. R. da Rocha, Omar Feres, Fernando C. Vilar, Gilberto G. Gaspar, Isabel K. F. M. Santos, Ana P. M. Fernandes, Sandra R. Maruyama, Elisa M. S. Russo, Vânia L. D. Bonato, Cristina R. B. Cardoso, Marcelo Dias-Baruffi, Lúcia H. Faccioli, Carlos A. Sorgi and on behalf of the ImmunoCovid Study Groupadd Show full author list remove Hide full author list
Viruses 2023, 15(2), 573; https://doi.org/10.3390/v15020573 - 19 Feb 2023
Cited by 3 | Viewed by 3116
Abstract
COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid [...] Read more.
COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid (eCB) system regulates various physiological processes including the immunological response. Additionally, during inflammatory and thrombotic processes, phospholipids from cell membranes are cleaved to produce platelet-activating factor (PAF), another lipid mediator. Nonetheless, the effect of GCs on this lipid pathway during COVID-19 therapy is still unknown. This is a cross-sectional study involving COVID-19 patients (n = 200) and healthy controls (n = 35). Target tandem mass spectrometry of plasma lipid mediators demonstrated that COVID-19 severity affected eCBs and PAF synthesis. This increased synthesis of eCB was adversely linked with systemic inflammatory markers IL-6 and sTREM-1 levels and neutrophil counts. The use of GCs altered these lipid pathways by reducing PAF and increasing 2-AG production. Corroborating this, transcriptome analysis of GC-treated patients blood leukocytes showed differential modulation of monoacylglycerol lipase and phospholipase A2 gene expression. Altogether, these findings offer a breakthrough in our understanding of COVID-19 pathophysiology, indicating that GCs may promote additional protective pharmacological effects by influencing the eCB and PAF pathways involved in the disease course. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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10 pages, 1198 KiB  
Article
EPAC1 Pharmacological Inhibition with AM-001 Prevents SARS-CoV-2 and Influenza A Virus Replication in Cells
by Charlotte Foret-Lucas, Thomas Figueroa, Alexandre Bertin, Pierre Bessière, Alexandre Lucas, Dorian Bergonnier, Marine Wasniewski, Alexandre Servat, Arnaud Tessier, Frank Lezoualc’h and Romain Volmer
Viruses 2023, 15(2), 319; https://doi.org/10.3390/v15020319 - 23 Jan 2023
Cited by 1 | Viewed by 1598
Abstract
The exceptional impact of the COVID-19 pandemic has stimulated an intense search for antiviral molecules. Host-targeted antiviral molecules have the potential of presenting broad-spectrum antiviral activity and are also considered as less likely to select for resistant viruses. In this study, we investigated [...] Read more.
The exceptional impact of the COVID-19 pandemic has stimulated an intense search for antiviral molecules. Host-targeted antiviral molecules have the potential of presenting broad-spectrum antiviral activity and are also considered as less likely to select for resistant viruses. In this study, we investigated the antiviral activity exerted by AM-001, a specific pharmacological inhibitor of EPAC1, a host exchange protein directly activated by cyclic AMP (cAMP). The cAMP-sensitive protein, EPAC1 regulates various physiological and pathological processes but its role in SARS-CoV-2 and influenza A virus infection has not yet been studied. Here, we provide evidence that the EPAC1 specific inhibitor AM-001 exerts potent antiviral activity against SARS-CoV-2 in the human lung Calu-3 cell line and the African green monkey Vero cell line. We observed a concentration-dependent inhibition of SARS-CoV-2 infectious viral particles and viral RNA release in the supernatants of AM-001 treated cells that was not associated with a significant impact on cellular viability. Furthermore, we identified AM-001 as an inhibitor of influenza A virus in Calu-3 cells. Altogether these results identify EPAC1 inhibition as a promising therapeutic target against viral infections. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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20 pages, 4475 KiB  
Article
Topoisomerase II as a Novel Antiviral Target against Panarenaviral Diseases
by Tosin Oladipo Afowowe, Yasuteru Sakurai, Shuzo Urata, Vahid Rajabali Zadeh and Jiro Yasuda
Viruses 2023, 15(1), 105; https://doi.org/10.3390/v15010105 - 30 Dec 2022
Cited by 1 | Viewed by 1693
Abstract
Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug Administration (FDA)-approved vaccine is not available. To identify novel therapeutic candidates against arenaviral diseases, an RNA polymerase [...] Read more.
Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug Administration (FDA)-approved vaccine is not available. To identify novel therapeutic candidates against arenaviral diseases, an RNA polymerase I-driven minigenome (MG) expression system for Lassa virus (LASV) was developed and optimized for high-throughput screening (HTS). Using this system, we screened 2595 FDA-approved compounds for inhibitors of LASV genome replication and identified multiple compounds including pixantrone maleate, a topoisomerase II inhibitor, as hits. Other tested topoisomerase II inhibitors also suppressed LASV MG activity. These topoisomerase II inhibitors also inhibited Junin virus (JUNV) MG activity and effectively limited infection by the JUNV Candid #1 strain, and siRNA knockdown of both topoisomerases (IIα and IIβ) restricted JUNV replication. These results suggest that topoisomerases II regulate arenavirus replication and can serve as molecular targets for panarenaviral replication inhibitors. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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17 pages, 2820 KiB  
Article
Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity
by Wiebke Obermann, Alexandra Friedrich, Ramakanth Madhugiri, Paul Klemm, Jan Philipp Mengel, Torsten Hain, Stephan Pleschka, Hans-Guido Wendel, Roland K. Hartmann, Susanne Schiffmann, John Ziebuhr, Christin Müller and Arnold Grünweller
Viruses 2022, 14(3), 519; https://doi.org/10.3390/v14030519 - 03 Mar 2022
Cited by 4 | Viewed by 2534
Abstract
Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like [...] Read more.
Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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14 pages, 1918 KiB  
Article
Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease
by Beatriz Sierra, Ana Cristina Magalhães, Daniel Soares, Bruno Cavadas, Ana B. Perez, Mayling Alvarez, Eglis Aguirre, Claudia Bracho, Luisa Pereira and Maria G. Guzman
Viruses 2021, 13(8), 1540; https://doi.org/10.3390/v13081540 - 04 Aug 2021
Cited by 1 | Viewed by 2409
Abstract
Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico–informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been [...] Read more.
Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico–informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, “Adrenergic receptor antagonist”, “ATPase inhibitor”, “NF-kB pathway inhibitor” and “Serotonin receptor antagonist”, were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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Review

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20 pages, 1202 KiB  
Review
Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets
by Jens Kleinehr, Janine J. Wilden, Yvonne Boergeling, Stephan Ludwig and Eike R. Hrincius
Viruses 2021, 13(10), 2068; https://doi.org/10.3390/v13102068 - 14 Oct 2021
Cited by 8 | Viewed by 3197
Abstract
Respiratory viruses are known to be the most frequent causative mediators of lung infections in humans, bearing significant impact on the host cell signaling machinery due to their host-dependency for efficient replication. Certain cellular functions are actively induced by respiratory viruses for their [...] Read more.
Respiratory viruses are known to be the most frequent causative mediators of lung infections in humans, bearing significant impact on the host cell signaling machinery due to their host-dependency for efficient replication. Certain cellular functions are actively induced by respiratory viruses for their own benefit. This includes metabolic pathways such as glycolysis, fatty acid synthesis (FAS) and the tricarboxylic acid (TCA) cycle, among others, which are modified during viral infections. Here, we summarize the current knowledge of metabolic pathway modifications mediated by the acute respiratory viruses respiratory syncytial virus (RSV), rhinovirus (RV), influenza virus (IV), parainfluenza virus (PIV), coronavirus (CoV) and adenovirus (AdV), and highlight potential targets and compounds for therapeutic approaches. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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27 pages, 2594 KiB  
Review
COVID-19: Mechanistic Model of the African Paradox Supports the Central Role of the NF-κB Pathway
by Ralf Kircheis, Manfred Schuster and Oliver Planz
Viruses 2021, 13(9), 1887; https://doi.org/10.3390/v13091887 - 21 Sep 2021
Cited by 12 | Viewed by 3915
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has expanded into a global pandemic, with more than 220 million affected persons and almost 4.6 million deaths by 8 September 2021. In particular, Europe and the Americas have been heavily affected by high [...] Read more.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has expanded into a global pandemic, with more than 220 million affected persons and almost 4.6 million deaths by 8 September 2021. In particular, Europe and the Americas have been heavily affected by high infection and death rates. In contrast, much lower infection rates and mortality have been reported generally in Africa, particularly in the sub-Saharan region (with the exception of the Southern Africa region). There are different hypotheses for this African paradox, including less testing, the young age of the population, genetic disposition, and behavioral and epidemiological factors. In the present review, we address different immunological factors and their correlation with genetic factors, pre-existing immune status, and differences in cytokine induction patterns. We also focus on epidemiological factors, such as specific medication coverage, helminth distribution, and malaria endemics in the sub-Saharan region. An analysis combining different factors is presented that highlights the central role of the NF-κB signaling pathway in the African paradox. Importantly, insights into the interplay of different factors with the underlying immune pathological mechanisms for COVID-19 can provide a better understanding of the disease and the development of new targets for more efficient treatment strategies. Full article
(This article belongs to the Special Issue Host Targeted Therapeutics against Virus Infections)
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