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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 (1 December 2020) | Viewed by 46466

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Special Issue Editors

Prof. Dr. Sara N. Richter

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Guest Editor

Department of Molecular Medicine, University of Padua, Padua, Italy
Interests: non-canonical nucleic acid structures; G-quadruplex; i-motifs; viruses; HIV-1; HSV-1; microorganisms; cancer; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Louis Flamand

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Guest Editor

Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine Laval University and Division of Infectious and Immune Diseases, CHU de Quebec Research Center-Université Laval, Quebec City, Canada
Interests: Human herpesviruses, HHV-6A/B, HSV-1, CMV, neurodegenerative diseases

Special Issue Information

Dear Colleagues,

The activity of current antiviral agents is limited to a few viruses, such as the human immunodeficiency virus (HIV), herpes viruses, hepatitis B/C viruses, and the influenza viruses. The available drugs target a limited number of viral steps, i.e., replication and transcription by inhibition of polymerases and integrases; protein maturation by targeting proteases; and entry, uncoating, and budding by modification or hindrance of virus attachment and surface proteins or cell receptors. While these activities effectively prevent/suppress viral replication, most of the time they do not eradicate the virus from the host, especially when chronic infections or latency are involved. Moreover, drug-resistant viruses, new virus variants, and new virus species that do not respond to any of the current antiviral treatments constantly emerge and are becoming an increasingly urgent priority.

In this Special Issue, we aim to explore new ways to combat viral infections. In particular, we welcome research on new compounds with antiviral activity, with unconventional targets and mechanisms of action against all types of viruses, including those for which a treatment is readily available and those for which no therapeutics currently exist.

Prof. Dr. Sara N. Richter
Prof. Dr. Louis Flamand
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

virus
antiviral drug
unconventional antiviral activity
new viral target
new antiviral mechanism
untreatable virus infections
latency
chronic infection
drug-resistant virus

Published Papers (10 papers)

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Research

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13 pages, 2905 KiB

Open AccessArticle

The SARS-CoV-2-Inactivating Activity of Hydroxytyrosol-Rich Aqueous Olive Pulp Extract (HIDROX^®) and Its Use as a Virucidal Cream for Topical Application

by Yohei Takeda, Dulamjav Jamsransuren, Sachiko Matsuda, Roberto Crea and Haruko Ogawa

Viruses 2021, 13(2), 232; https://doi.org/10.3390/v13020232 - 02 Feb 2021

Cited by 26 | Viewed by 4296

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally. Although measures to control SARS-CoV-2, namely, vaccination, medication, and chemical disinfectants are being investigated, there is an increase in the demand for auxiliary antiviral approaches using natural compounds. Here we have focused on hydroxytyrosol (HT)-rich aqueous olive pulp extract (HIDROX^®) and evaluated its SARS-CoV-2-inactivating activity in vitro. We showed that the HIDROX solution exhibits time- and concentration-dependent SARS-CoV-2-inactivating activities, and that HIDROX has more potent virucidal activity than pure HT. The evaluation of the mechanism of action suggested that both HIDROX and HT induced structural changes in SARS-CoV-2, which changed the molecular weight of the spike proteins. Even though the spike protein is highly glycosylated, this change was induced regardless of the glycosylation status. In addition, HIDROX or HT treatment disrupted the viral genome. Moreover, the HIDROX-containing cream applied on film showed time- and concentration-dependent SARS-CoV-2-inactivating activities. Thus, the HIDROX-containing cream can be applied topically as an antiviral hand cream. Our findings suggest that HIDROX contributes to improving SARS-CoV-2 control measures. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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19 pages, 12303 KiB

Open AccessArticle

Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

by Sara Artusi, Emanuela Ruggiero, Matteo Nadai, Beatrice Tosoni, Rosalba Perrone, Annalisa Ferino, Irene Zanin, Luigi Xodo, Louis Flamand and Sara N. Richter

Viruses 2021, 13(2), 196; https://doi.org/10.3390/v13020196 - 28 Jan 2021

Cited by 32 | Viewed by 3213

Abstract

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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15 pages, 4459 KiB

Open AccessArticle

Chloroquine and Sulfadoxine Derivatives Inhibit ZIKV Replication in Cervical Cells

by Audrien Alves Andrade de Souza, Lauana Ribas Torres, Lyana Rodrigues Pinto Lima Capobianco, Vanessa Salete de Paula, Cynthia Machado Cascabulho, Kelly Salomão, Maria da Gloria Bonecini-Almeida, Maria de Lourdes Garcia Ferreira, Nubia Boechat, Luiz Carlos da Silva Pinheiro and Elen Mello de Souza

Viruses 2021, 13(1), 36; https://doi.org/10.3390/v13010036 - 29 Dec 2020

Cited by 5 | Viewed by 2067

Abstract

Despite the severe morbidity caused by Zika fever, its specific treatment is still a challenge for public health. Several research groups have investigated the drug repurposing of chloroquine. However, the highly toxic side effect induced by chloroquine paves the way for the improvement of this drug for use in Zika fever clinics. Our aim is to evaluate the anti-Zika virus (ZIKV) effect of hybrid compounds derived from chloroquine and sulfadoxine antimalarial drugs. The antiviral activity of hybrid compounds (C-Sd1 to C-Sd7) was assessed in an in-vitro model of human cervical and Vero cell lines infected with a Brazilian (BR) ZIKV strain. First, we evaluated the cytotoxic effect on cultures treated with up to 200 µM of C-Sds and observed CC₅₀ values that ranged from 112.0 ± 1.8 to >200 µM in cervical cells and 43.2 ± 0.4 to 143.0 ± 1.3 µM in Vero cells. Then, the cultures were ZIKV-infected and treated with up to 25 µM of C-Sds for 48 h. The treatment of cervical cells with C-Sds at 12 µM induced a reduction of 79.8% ± 4.2% to 90.7% ± 1.5% of ZIKV–envelope glycoprotein expression in infected cells as compared to 36.8% ± 2.9% of infection in vehicle control. The viral load was also investigated and revealed a reduction of 2- to 3-logs of ZIKV genome copies/mL in culture supernatants compared to 6.7 ± 0.7 × 10⁸ copies/mL in vehicle control. The dose–response curve by plaque-forming reduction (PFR) in cervical cells revealed a potent dose-dependent activity of C-Sds in inhibiting ZIKV replication, with PFR above 50% and 90% at 6 and 12 µM, respectively, while 25 µM inhibited 100% of viral progeny. The treatment of Vero cells at 12 µM led to 100% PFR, confirming the C-Sds activity in another cell type. Regarding effective concentration in cervical cells, the EC₅₀ values ranged from 3.2 ± 0.1 to 5.0 ± 0.2 µM, and the EC₉₀ values ranged from 7.2 ± 0.1 to 11.6 ± 0.1 µM, with selectivity index above 40 for most C-Sds, showing a good therapeutic window. Here, our aim is to investigate the anti-ZIKV activity of new hybrid compounds that show highly potent efficacy as inhibitors of ZIKV in-vitro infection. However, further studies will be needed to investigate whether these new chemical structures can lead to the improvement of chloroquine antiviral activity. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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18 pages, 2673 KiB

Open AccessArticle

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

by Friedrich Hahn, Christina Wangen, Sigrun Häge, Antonia Sophia Peter, Gerhard Dobler, Brett Hurst, Justin Julander, Jonas Fuchs, Zsolt Ruzsics, Klaus Überla, Hans-Martin Jäck, Roger Ptak, Andreas Muehler, Manfred Gröppel, Daniel Vitt, Evelyn Peelen, Hella Kohlhof and Manfred Marschall

Viruses 2020, 12(12), 1394; https://doi.org/10.3390/v12121394 - 05 Dec 2020

Cited by 36 | Viewed by 5825

Abstract

The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human dihydroorotate dehydrogenase (DHODH) with a recently proven antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC_50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC_50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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13 pages, 2306 KiB

Open AccessArticle

A Synthetic Bioactive Peptide Derived from the Asian Medicinal Plant Acacia catechu Binds to Dengue Virus and Inhibits Cell Entry

by Aussara Panya, Nunghathai Sawasdee, Pucharee Songprakhon, Yingmanee Tragoolpua, Siriphorn Rotarayanont, Kiattawee Choowongkomon and Pa-thai Yenchitsomanus

Viruses 2020, 12(11), 1267; https://doi.org/10.3390/v12111267 - 06 Nov 2020

Cited by 9 | Viewed by 2559

Abstract

Dengue virus (DENV) infection has become a critically important globally prevalent infectious disease, especially in tropical and subtropical countries. Since neither currently exists, there is an urgent need for an effective vaccine to prevent, and a specific drug to treat DENV infection. Therapeutic peptides represent an attractive alternative for development into anti-DENV drugs due to their safety and their diverse biological and chemical properties. We recently reported novel bioactive peptides extracted from the Asian medicinal plant Acacia catechu that efficiently inhibited all four DENV serotypes. In this study, we investigated the anti-DENV activity of a synthetic bioactive peptide derived from this plant. The most effective peptide (designated Pep-RTYM) inhibited DENV infection with a half-maximal inhibition concentration value of 7.9 μM. Time-of-addition study demonstrated that Pep-RTYM interacted with DENV particles and inhibited cellular entry. Pep-RTYM at 50 μM significantly reduced DENV production in Vero-kidney epithelial cells about 1000-fold, but it could decrease the virus production in Huh7 hepatocyte cells approximately 40-fold. Binding of Pep-RTYM to DENV particles may prevent virus interaction with cellular receptor and subsequent virus entry. This finding suggests a potential role of Pep-RTYM in the development of a novel anti-DENV drug. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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14 pages, 3731 KiB

Open AccessArticle

In Vitro Inhibition of Zika Virus Replication with Poly(Sodium 4-Styrenesulfonate)

by Paweł Botwina, Magdalena Obłoza, Artur Szczepański, Krzysztof Szczubiałka, Maria Nowakowska and Krzysztof Pyrć

Viruses 2020, 12(9), 926; https://doi.org/10.3390/v12090926 - 23 Aug 2020

Cited by 4 | Viewed by 3484

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne pathogen associated with microcephaly and other congenital abnormalities in newborns as well as neurologic complications in adults. The explosive transmission of the virus in the last ten years put it in the limelight and improved our understanding of its biology and pathology. Currently, no vaccine or drugs are available to prevent or treat ZIKV infections. Knowing the potential of flaviviruses to broaden their geographic distribution, as observed for the West Nile virus, it is of importance to develop novel antiviral strategies. In this work, we identified poly(sodium 4-styrenesulfonate) (PSSNa) as a new polymeric ZIKV inhibitor. We demonstrated that PSSNa inhibits ZIKV replication in vitro both in animal and human cells, while no cytotoxicity is observed. Our mechanistic studies indicated that PSSNa acts mostly through direct binding to ZIKV particle and blocking its attachment to the host cells. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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18 pages, 2816 KiB

Open AccessArticle

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

by Anna Glanz, Karan Chawla, Stephanie Fabry, Gayatri Subramanian, Julie Garcia, Bryanna Jay, Jacob Ciricillo, Ritu Chakravarti, R. Travis Taylor and Saurabh Chattopadhyay

Viruses 2020, 12(4), 442; https://doi.org/10.3390/v12040442 - 14 Apr 2020

Cited by 12 | Viewed by 4337

Abstract

Interferon (IFN) regulatory factor 3 (IRF3) is the key transcription factor for the induction of IFN and antiviral genes. The absence of antiviral genes in IRF3 deficiency leads to susceptibility to a wide range of viral infections. Previously, we uncovered a function for nontranscriptional IRF3 (nt-IRF3), RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA), which triggers apoptotic killing of virus-infected cells. Using knock-in mice expressing a transcriptionally inactive, but RIPA-active, IRF3 mutant, we demonstrated the relative contribution of RIPA to host antiviral defense. Given that RIPA is a cellular antiviral pathway, we hypothesized that small molecules that promote RIPA in virus-infected cells would act as antiviral agents. To test this, we conducted a high throughput screen of a library of FDA-approved drugs to identify novel RIPA activators. Our screen identified doxorubicin as a potent RIPA-activating agent. In support of our hypothesis, doxorubicin inhibited the replication of vesicular stomatitis virus, a model rhabdovirus, and its antiviral activity depended on its ability to activate IRF3 in RIPA. Surprisingly, doxorubicin inhibited the transcriptional activity of IRF3. The antiviral activity of doxorubicin was expanded to flavivirus and herpesvirus that also activate IRF3. Mechanistically, doxorubicin promoted RIPA by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Finally, we validated these results using another RIPA-activating compound, pyrvinium pamoate, which showed a similar antiviral effect without affecting the transcriptional activity of IRF3. Therefore, we demonstrate that the RIPA branch of IRF3 can be targeted therapeutically to prevent virus infection. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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18 pages, 1432 KiB

Open AccessReview

The Fatty Acid Lipid Metabolism Nexus in COVID-19

by Jerome E. Tanner and Caroline Alfieri

Viruses 2021, 13(1), 90; https://doi.org/10.3390/v13010090 - 11 Jan 2021

Cited by 56 | Viewed by 8165

Abstract

Enteric symptomology seen in early-stage severe acute respiratory syndrome (SARS)-2003 and COVID-19 is evidence of virus replication occurring in the intestine, liver and pancreas. Aberrant lipid metabolism in morbidly obese individuals adversely affects the COVID-19 immune response and increases disease severity. Such observations are in line with the importance of lipid metabolism in COVID-19, and point to the gut as a site for intervention as well as a therapeutic target in treating the disease. Formation of complex lipid membranes and palmitoylation of coronavirus proteins are essential during viral replication and assembly. Inhibition of fatty acid synthase (FASN) and restoration of lipid catabolism by activation of AMP-activated protein kinase (AMPK) impede replication of coronaviruses closely related to SARS-coronavirus-2 (CoV-2). In vitro findings and clinical data reveal that the FASN inhibitor, orlistat, and the AMPK activator, metformin, may inhibit coronavirus replication and reduce systemic inflammation to restore immune homeostasis. Such observations, along with the known mechanisms of action for these types of drugs, suggest that targeting fatty acid lipid metabolism could directly inhibit virus replication while positively impacting the patient’s response to COVID-19. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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19 pages, 409 KiB

Open AccessReview

Resveratrol, Rapamycin and Metformin as Modulators of Antiviral Pathways

by Francesca Benedetti, Vincenzo Sorrenti, Alessandro Buriani, Stefano Fortinguerra, Giovanni Scapagnini and Davide Zella

Viruses 2020, 12(12), 1458; https://doi.org/10.3390/v12121458 - 17 Dec 2020

Cited by 12 | Viewed by 5258

Abstract

Balanced nutrition and appropriate dietary interventions are fundamental in the prevention and management of viral infections. Additionally, accurate modulation of the inflammatory response is necessary to achieve an adequate antiviral immune response. Many studies, both in vitro with mammalian cells and in vivo with small animal models, have highlighted the antiviral properties of resveratrol, rapamycin and metformin. The current review outlines the mechanisms of action of these three important compounds on the cellular pathways involved with viral replication and the mechanisms of virus-related diseases, as well as the current status of their clinical use. Full article

(This article belongs to the Special Issue Unconventional Antiviral Agents)

15 pages, 476 KiB

Open AccessReview

Curcumin as an Antiviral Agent

by Morgan R. Jennings and Robin J. Parks

Viruses 2020, 12(11), 1242; https://doi.org/10.3390/v12111242 - 31 Oct 2020

Cited by 104 | Viewed by 6354

Abstract

Curcumin, the primary curcuminoid compound found in turmeric spice, has shown broad activity as an antimicrobial agent, limiting the replication of many different fungi, bacteria and viruses. In this review, we summarize recent studies supporting the development of curcumin and its derivatives as [...] Read more.

(This article belongs to the Special Issue Unconventional Antiviral Agents)

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