Antiviral Therapeutics for Emerging Viruses

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 (20 December 2021) | Viewed by 30411

Special Issue Editors

Unité des Virus Emergents, Aix-Marseille University-IRD 190-Inserm 1207, IHU Méditerranée Infection, 13005 Marseille, France
Interests: emerging viruses; antivirals; structural and molecular virology; preparedness
Special Issues, Collections and Topics in MDPI journals
Unité des Virus Émergents, Aix-Marseille Univ, IRD 190-Inserm 1207, IHU Méditerranée Infection, 13000 Marseille, France
Interests: antivirals; reverse genetics; animal models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The emergence and re-emergence of viruses represent a major concern for the human population, as illustrated by frequent outbreaks since the beginning of the century. Modifications of climate, lifestyle, population density, and vicinity to wild animals and livestock contribute to the increasing number of viral emergences. Unfortunately, the recent SARS-CoV-2 outbreak has highlighted that there is still a major gap to fill to be better prepared for and respond to such events. Regarding antivirals, it implies the development of broad-spectrum antiviral drugs for unexpected emerging agents as well as optimized therapeutics to cure targeted agents with a high probability of (re)emergence. In this Special Issue, we would like to promote the development and characterization of antivirals against emerging viruses or viruses with the potential for emergence. The issue will focus on the early stages of the drug development to the preclinical studies, including target discovery, antiviral screening and optimization, and mode of action. The development of innovative technologies related to the antiviral field such as screening assays, animal models, and reverse genetics systems is also welcome. As the scope of this Special Issue, “Antiviral Therapeutics against Emerging Viruses”, is quite vast, we will restrict it to zoonotic and human diseases.

Prof. Dr. Bruno Coutard
Dr. Franck Touret
Guest Editors

Manuscript Submission Information

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Keywords

  • emerging viruses
  • antiviral screening
  • drug design
  • animal model
  • mode of action

Related Special Issue

Published Papers (9 papers)

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Research

22 pages, 9300 KiB  
Article
Ebola Virus GP Activates Endothelial Cells via Host Cytoskeletal Signaling Factors
by Benedicte Mpia Moni, Yasuteru Sakurai and Jiro Yasuda
Viruses 2022, 14(1), 142; https://0-doi-org.brum.beds.ac.uk/10.3390/v14010142 - 13 Jan 2022
Cited by 3 | Viewed by 2954
Abstract
Ebola virus disease (EVD) is a lethal disease caused by the highly pathogenic Ebola virus (EBOV), and its major symptoms in severe cases include vascular leakage and hemorrhage. These symptoms are caused by abnormal activation and disruption of endothelial cells (ECs) whose mediators [...] Read more.
Ebola virus disease (EVD) is a lethal disease caused by the highly pathogenic Ebola virus (EBOV), and its major symptoms in severe cases include vascular leakage and hemorrhage. These symptoms are caused by abnormal activation and disruption of endothelial cells (ECs) whose mediators include EBOV glycoprotein (GP) without the need for viral replication. However, the detailed molecular mechanisms underlying virus–host interactions remain largely unknown. Here, we show that EBOV-like particles (VLPs) formed by GP, VP40, and NP activate ECs in a GP-dependent manner, as demonstrated by the upregulation of intercellular adhesion molecules-1 (ICAM-1) expression. VLPs-mediated ECs activation showed a different kinetic pattern from that of TNF-α-mediated activation and was associated with apoptotic ECs disruption. In contrast to TNF-α, VLPs induced ICAM-1 overexpression at late time points. Furthermore, screening of host cytoskeletal signaling inhibitors revealed that focal adhesion kinase inhibitors were found to be potent inhibitors of ICAM-1 expression mediated by both TNF-α and VLPs. Our results suggest that EBOV GP stimulates ECs to induce endothelial activation and dysfunction with the involvement of host cytoskeletal signaling factors, which represent potential therapeutic targets for EVD. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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15 pages, 2447 KiB  
Article
Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro
by Bruno A. Rodriguez-Rodriguez, Maria G. Noval, Maria E. Kaczmarek, Kyung Ku Jang, Sara A. Thannickal, Angelica Cifuentes Kottkamp, Rebecca S. Brown, Margaret Kielian, Ken Cadwell and Kenneth A. Stapleford
Viruses 2021, 13(12), 2437; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122437 - 04 Dec 2021
Cited by 10 | Viewed by 2823
Abstract
Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is [...] Read more.
Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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19 pages, 29559 KiB  
Communication
Drug-Screening Strategies for Inhibition of Virus-Induced Neuronal Cell Death
by Durbadal Ojha, Tyson A. Woods and Karin E. Peterson
Viruses 2021, 13(11), 2317; https://0-doi-org.brum.beds.ac.uk/10.3390/v13112317 - 20 Nov 2021
Cited by 4 | Viewed by 2910
Abstract
A number of viruses, including Herpes Simplex Virus (HSV), West Nile Virus (WNV), La Crosse Virus (LACV), Zika virus (ZIKV) and Tick-borne encephalitis virus (TBEV), have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease or [...] Read more.
A number of viruses, including Herpes Simplex Virus (HSV), West Nile Virus (WNV), La Crosse Virus (LACV), Zika virus (ZIKV) and Tick-borne encephalitis virus (TBEV), have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease or death. Although encephalitis cases caused by these viruses are generally rare, there are relatively few treatment options available for patients with viral encephalitis other than palliative care. Many of these viruses directly infect neurons and can cause neuronal death. Thus, there is the need for the identification of useful therapeutic compounds that can inhibit virus replication in neurons or inhibit virus-induced neuronal cell death. In this paper, we describe the methodology to test compounds for their ability to inhibit virus-induced neuronal cell death. These protocols include the isolation and culturing of primary neurons; the culturing of neuroblastoma and neuronal stem cell lines; infection of these cells with viruses; treatment of these cells with selected drugs; measuring virus-induced cell death using MTT or XTT reagents; analysis of virus production from these cells; as well as the basic understanding in mode of action. We further show direct evidence of the effectiveness of these protocols by utilizing them to test the effectiveness of the polyphenol drug, Rottlerin, at inhibiting Zika virus infection and death of neuronal cell lines. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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15 pages, 1701 KiB  
Article
Inhibition of SARS-CoV-2 Replication by a Small Interfering RNA Targeting the Leader Sequence
by Beatrice Tolksdorf, Chuanxiong Nie, Daniela Niemeyer, Viola Röhrs, Johanna Berg, Daniel Lauster, Julia M. Adler, Rainer Haag, Jakob Trimpert, Benedikt Kaufer, Christian Drosten and Jens Kurreck
Viruses 2021, 13(10), 2030; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102030 - 08 Oct 2021
Cited by 21 | Viewed by 4705
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected almost 200 million people worldwide and led to approximately 4 million deaths as of August 2021. Despite successful vaccine development, treatment options are limited. A promising strategy to specifically target viral infections is to [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected almost 200 million people worldwide and led to approximately 4 million deaths as of August 2021. Despite successful vaccine development, treatment options are limited. A promising strategy to specifically target viral infections is to suppress viral replication through RNA interference (RNAi). Hence, we designed eight small interfering RNAs (siRNAs) targeting the highly conserved 5′-untranslated region (5′-UTR) of SARS-CoV-2. The most promising candidate identified in initial reporter assays, termed siCoV6, targets the leader sequence of the virus, which is present in the genomic as well as in all subgenomic RNAs. In assays with infectious SARS-CoV-2, it reduced replication by two orders of magnitude and prevented the development of a cytopathic effect. Moreover, it retained its activity against the SARS-CoV-2 alpha variant and has perfect homology against all sequences of the delta variant that were analyzed by bioinformatic means. Interestingly, the siRNA was even highly active in virus replication assays with the SARS-CoV-1 family member. This work thus identified a very potent siRNA with a broad activity against various SARS-CoV viruses that represents a promising candidate for the development of new treatment options. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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22 pages, 2835 KiB  
Article
A Bioluminescent 3CLPro Activity Assay to Monitor SARS-CoV-2 Replication and Identify Inhibitors
by Cyrille Mathieu, Franck Touret, Clémence Jacquemin, Yves L. Janin, Antoine Nougairède, Manon Brailly, Magalie Mazelier, Didier Décimo, Virginie Vasseur, Aymeric Hans, José-Carlos Valle-Casuso, Xavier de Lamballerie, Branka Horvat, Patrice André, Mustapha Si-Tahar, Vincent Lotteau and Pierre-Olivier Vidalain
Viruses 2021, 13(9), 1814; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091814 - 12 Sep 2021
Cited by 9 | Viewed by 4100
Abstract
Our therapeutic arsenal against viruses is very limited and the current pandemic of SARS-CoV-2 highlights the critical need for effective antivirals against emerging coronaviruses. Cellular assays allowing a precise quantification of viral replication in high-throughput experimental settings are essential to the screening of [...] Read more.
Our therapeutic arsenal against viruses is very limited and the current pandemic of SARS-CoV-2 highlights the critical need for effective antivirals against emerging coronaviruses. Cellular assays allowing a precise quantification of viral replication in high-throughput experimental settings are essential to the screening of chemical libraries and the selection of best antiviral chemical structures. To develop a reporting system for SARS-CoV-2 infection, we generated cell lines expressing a firefly luciferase maintained in an inactive form by a consensus cleavage site for the viral protease 3CLPro of coronaviruses, so that the luminescent biosensor is turned on upon 3CLPro expression or SARS-CoV-2 infection. This cellular assay was used to screen a metabolism-oriented library of 492 compounds to identify metabolic vulnerabilities of coronaviruses for developing innovative therapeutic strategies. In agreement with recent reports, inhibitors of pyrimidine biosynthesis were found to prevent SARS-CoV-2 replication. Among the top hits, we also identified the NADPH oxidase (NOX) inhibitor Setanaxib. The anti-SARS-CoV-2 activity of Setanaxib was further confirmed using ACE2-expressing human pulmonary cells Beas2B as well as human primary nasal epithelial cells. Altogether, these results validate our cell-based functional assay and the interest of screening libraries of different origins to identify inhibitors of SARS-CoV-2 for drug repurposing or development. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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13 pages, 14179 KiB  
Article
CP100356 Hydrochloride, a P-Glycoprotein Inhibitor, Inhibits Lassa Virus Entry: Implication of a Candidate Pan-Mammarenavirus Entry Inhibitor
by Toru Takenaga, Zihan Zhang, Yukiko Muramoto, Sarah Katharina Fehling, Ai Hirabayashi, Yuki Takamatsu, Junichi Kajikawa, Sho Miyamoto, Masahiro Nakano, Shuzo Urata, Allison Groseth, Thomas Strecker and Takeshi Noda
Viruses 2021, 13(9), 1763; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091763 - 03 Sep 2021
Cited by 2 | Viewed by 2356
Abstract
Lassa virus (LASV)—a member of the family Arenaviridae—causes Lassa fever in humans and is endemic in West Africa. Currently, no approved drugs are available. We screened 2480 small compounds for their potential antiviral activity using pseudotyped vesicular stomatitis virus harboring the LASV [...] Read more.
Lassa virus (LASV)—a member of the family Arenaviridae—causes Lassa fever in humans and is endemic in West Africa. Currently, no approved drugs are available. We screened 2480 small compounds for their potential antiviral activity using pseudotyped vesicular stomatitis virus harboring the LASV glycoprotein (VSV-LASVGP) and a related prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). Follow-up studies confirmed that CP100356 hydrochloride (CP100356), a specific P-glycoprotein (P-gp) inhibitor, suppressed VSV-LASVGP, LCMV, and LASV infection with half maximal inhibitory concentrations of 0.52, 0.54, and 0.062 μM, respectively, without significant cytotoxicity. Although CP100356 did not block receptor binding at the cell surface, it inhibited low-pH-dependent membrane fusion mediated by arenavirus glycoproteins. P-gp downregulation did not cause a significant reduction in either VSV-LASVGP or LCMV infection, suggesting that P-gp itself is unlikely to be involved in arenavirus entry. Finally, our data also indicate that CP100356 inhibits the infection by other mammarenaviruses. Thus, our findings suggest that CP100356 can be considered as an effective virus entry inhibitor for LASV and other highly pathogenic mammarenaviruses. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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20 pages, 5582 KiB  
Article
Identification of Novel HBV/HDV Entry Inhibitors by Pharmacophore- and QSAR-Guided Virtual Screening
by Michael Kirstgen, Simon Franz Müller, Kira Alessandra Alicia Theresa Lowjaga, Nora Goldmann, Felix Lehmann, Sami Alakurtti, Jari Yli-Kauhaluoma, Karl-Heinz Baringhaus, Reimar Krieg, Dieter Glebe and Joachim Geyer
Viruses 2021, 13(8), 1489; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081489 - 29 Jul 2021
Cited by 7 | Viewed by 2927
Abstract
The hepatic bile acid transporter Na+/taurocholate co-transporting polypeptide (NTCP) was identified in 2012 as the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Since then, this carrier has emerged as promising drug target for HBV/HDV virus entry inhibitors, [...] Read more.
The hepatic bile acid transporter Na+/taurocholate co-transporting polypeptide (NTCP) was identified in 2012 as the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Since then, this carrier has emerged as promising drug target for HBV/HDV virus entry inhibitors, but the synthetic peptide Hepcludex® of high molecular weight is the only approved HDV entry inhibitor so far. The present study aimed to identify small molecules as novel NTCP inhibitors with anti-viral activity. A ligand-based bioinformatic approach was used to generate and validate appropriate pharmacophore and QSAR (quantitative structure–activity relationship) models. Half-maximal inhibitory concentrations (IC50) for binding inhibition of the HBV/HDV-derived preS1 peptide (as surrogate parameter for virus binding to NTCP) were determined in NTCP-expressing HEK293 cells for 150 compounds of different chemical classes. IC50 values ranged from 2 µM up to >1000 µM. The generated pharmacophore and QSAR models were used for virtual screening of drug-like chemicals from the ZINC15 database (~11 million compounds). The 20 best-performing compounds were then experimentally tested for preS1-peptide binding inhibition in NTCP-HEK293 cells. Among them, four compounds were active and revealed experimental IC50 values for preS1-peptide binding inhibition of 9, 19, 20, and 35 µM, which were comparable to the QSAR-based predictions. All these compounds also significantly inhibited in vitro HDV infection of NTCP-HepG2 cells, without showing any cytotoxicity. The best-performing compound in all assays was ZINC000253533654. In conclusion, the present study demonstrates that virtual compound screening based on NTCP-specific pharmacophore and QSAR models can predict novel active hit compounds for the development of HBV/HDV entry inhibitors. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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13 pages, 3521 KiB  
Article
Antiviral Activity of Chrysin against Influenza Virus Replication via Inhibition of Autophagy
by Seong-Ryeol Kim, Myeong-Seon Jeong, Seo-Hyeon Mun, Jaewon Cho, Min-Duk Seo, Hyoungsu Kim, Jooeun Lee, Jae-Hyoung Song and Hyun-Jeong Ko
Viruses 2021, 13(7), 1350; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071350 - 13 Jul 2021
Cited by 14 | Viewed by 3125
Abstract
Influenza viruses cause respiratory infections in humans and animals, which have high morbidity and mortality rates. Although several drugs that inhibit viral neuraminidase are used to treat influenza infections, the emergence of resistant viruses necessitates the urgent development of new antiviral drugs. Chrysin [...] Read more.
Influenza viruses cause respiratory infections in humans and animals, which have high morbidity and mortality rates. Although several drugs that inhibit viral neuraminidase are used to treat influenza infections, the emergence of resistant viruses necessitates the urgent development of new antiviral drugs. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid that exhibits antiviral activity against enterovirus 71 (EV71) by inhibiting viral 3C protease activity. In this study, we evaluated the antiviral activity of chrysin against influenza A/Puerto Rico/8/34 (A/PR/8). Chrysin significantly inhibited A/PR/8-mediated cell death and the replication of A/PR/8 at concentrations up to 2 μM. Viral hemagglutinin expression was also markedly decreased by the chrysin treatment in A/PR/8-infected cells. Through the time course experiment and time-of-addition assay, we found that chrysin inhibited viral infection at the early stages of the replication cycle. Additionally, the nucleoprotein expression of A/PR/8 in A549 cells was reduced upon treatment with chrysin. Regarding the mechanism of action, we found that chrysin inhibited autophagy activation by increasing the phosphorylation of mammalian target of rapamycin (mTOR). We also confirmed a decrease in LC3B expression and LC3-positive puncta levels in A/PR/8-infected cells. These results suggest that chrysin exhibits antiviral activity by activating mTOR and inhibiting autophagy to inhibit the replication of A/PR/8 in the early stages of infection. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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14 pages, 2189 KiB  
Article
Inhibitory Effect of Sargassum fusiforme and Its Components on Replication of Respiratory Syncytial Virus In Vitro and In Vivo
by Kiramage Chathuranga, Asela Weerawardhana, Niranjan Dodantenna, Lakmal Ranathunga, Won-Kyung Cho, Jin Yeul Ma and Jong-Soo Lee
Viruses 2021, 13(4), 548; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040548 - 25 Mar 2021
Cited by 13 | Viewed by 3139
Abstract
Sargassum fusiforme, a plant used as a medicine and food, is regarded as a marine vegetable and health supplement to improve life expectancy. Here, we demonstrate that S. fusiforme extract (SFE) has antiviral effects against respiratory syncytial virus (RSV) in vitro and [...] Read more.
Sargassum fusiforme, a plant used as a medicine and food, is regarded as a marine vegetable and health supplement to improve life expectancy. Here, we demonstrate that S. fusiforme extract (SFE) has antiviral effects against respiratory syncytial virus (RSV) in vitro and in vivo mouse model. Treatment of HEp2 cells with a non-cytotoxic concentration of SFE significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and syncytium formation. Moreover, oral inoculation of SFE significantly improved RSV clearance from the lungs of BALB/c mice. Interestingly, the phenolic compounds eicosane, docosane, and tetracosane were identified as active components of SFE. Treatment with a non-cytotoxic concentration of these three components elicited similar antiviral effects against RSV infection as SFE in vitro. Together, these results suggest that SFE and its potential components are a promising natural antiviral agent candidate against RSV infection. Full article
(This article belongs to the Special Issue Antiviral Therapeutics for Emerging Viruses)
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