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Recent Advances in Antiviral Agents
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Recent Advances in Antiviral Agents

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 71971

Special Issue Editor

Dr. Luděk Eyer

E-Mail Website
Guest Editor
Veterinary Research Institute, Brno, Czech Republic AND Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
Interests: antiviral research; nucleoside analog; tick-borne encephalitis virus; small molecule-based inhibitor; non-nucleoside antivirals; Flaviviridae

Special Issue Information

Dear Colleagues,

Antivirals represent a crucial therapeutic tool to effectively combat serious and life-threatening viral diseases. Recent outbreaks of several emerging viruses, such as Ebola virus, Zika virus, influenza viruses, or SARS-CoV-2, highlight the importance of the development of novel highly effective antiviral agents. As nucleoside analogs are still the most abundant drugs in the field of antiviral research, non-nucleoside virus inhibitors, host-targeting antivirals, and natural compounds with well-understood modes of action are also promising candidates to treat infections caused by medically important viral pathogens. This Special Issue will publish contributions describing and discussing all the aspects that are broadly indicated by the listed keywords. Review articles by experts in the field of antiviral research are also welcome.

Dr. Luděk Eyer
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.

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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

  • Nucleoside analog
  • Non-nucleoside antivirals
  • Natural antivirals
  • Direct antiviral agents
  • Host-targeting antivirals
  • Mechanism of action
  • Combination therapy
  • Antiviral resistance
  • Animal infection model

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Published Papers (7 papers)

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Research

Jump to: Review

10 pages, 1776 KiB  
Article
Dietary Supplementation of Aspirin Promotes Drosophila Defense against Viral Infection
by Fanrui Kong, Abdul Qadeer, Yali Xie, Yiheng Jin, Qingyang Li, Yihua Xiao, Kan She, Xianrui Zheng, Jiashu Li, Shanming Ji and Yangyang Zhu
Molecules 2023, 28(14), 5300; https://doi.org/10.3390/molecules28145300 - 9 Jul 2023
Cited by 5 | Viewed by 1947
Abstract
Aspirin, also known as acetylsalicylic acid, is widely consumed as a pain reliever and an anti-inflammatory as well as anti-platelet agent. Recently, our studies using the animal model of Drosophila demonstrated that the dietary supplementation of aspirin renovates age-onset intestinal dysfunction and delays [...] Read more.
Aspirin, also known as acetylsalicylic acid, is widely consumed as a pain reliever and an anti-inflammatory as well as anti-platelet agent. Recently, our studies using the animal model of Drosophila demonstrated that the dietary supplementation of aspirin renovates age-onset intestinal dysfunction and delays organismal aging. Nevertheless, it remains probable that aspirin plays functional roles in other biological activities, for instance antiviral defense reactions. Intriguingly, we observed that the replications of several types of viruses were drastically antagonized in Drosophila macrophage-like S2 cells with the addition of aspirin. Further in vivo experimental approaches illustrate that adult flies consuming aspirin harbor higher resistances to viral infections with respect to flies without aspirin treatment. Mechanistically, aspirin positively contributes to the Drosophila antiviral defense largely through mediating the STING (stimulator of interferon genes) but not the IMD (immune deficiency) signaling pathway. Collectively, our studies uncover a novel biological function of aspirin in modulating Drosophila antiviral immunity and provide theoretical bases for exploring new antiviral treatments in clinical trials. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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18 pages, 4640 KiB  
Article
Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors
by Marjorie C. L. C. Freire, Gabriela D. Noske, Natália V. Bitencourt, Paulo R. S. Sanches, Norival A. Santos-Filho, Victor O. Gawriljuk, Eduardo P. de Souza, Victor H. R. Nogueira, Mariana O. de Godoy, Aline M. Nakamura, Rafaela S. Fernandes, Andre S. Godoy, Maria A. Juliano, Bianca M. Peres, Cecília G. Barbosa, Carolina B. Moraes, Lucio H. G. Freitas-Junior, Eduardo M. Cilli, Rafael V. C. Guido and Glaucius Oliva
Molecules 2021, 26(16), 4896; https://doi.org/10.3390/molecules26164896 - 12 Aug 2021
Cited by 22 | Viewed by 32967
Abstract
The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of [...] Read more.
The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28–65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0–3.5 µM) and binding affinities (Kd = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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22 pages, 4725 KiB  
Article
4,7-Disubstituted 7H-Pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents against Zika Virus
by Ruben Soto-Acosta, Eunkyung Jung, Li Qiu, Daniel J. Wilson, Robert J. Geraghty and Liqiang Chen
Molecules 2021, 26(13), 3779; https://doi.org/10.3390/molecules26133779 - 22 Jun 2021
Cited by 9 | Viewed by 2378
Abstract
Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an [...] Read more.
Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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9 pages, 675 KiB  
Article
Topical Astodrimer Sodium, a Non-Toxic Polyanionic Dendrimer, Demonstrates Antiviral Activity in an Experimental Ocular Adenovirus Infection Model
by Eric G. Romanowski, Kathleen A. Yates, Jeremy R. A. Paull, Graham P. Heery and Robert M. Q. Shanks
Molecules 2021, 26(11), 3419; https://doi.org/10.3390/molecules26113419 - 5 Jun 2021
Cited by 7 | Viewed by 4176
Abstract
There is no approved antiviral therapy for adenovirus (HAdV) ocular infections. Astodrimer sodium (SPL7013) is a polyanionic dendrimer with antiviral activity. The current study evaluated the ocular tolerability and anti-adenoviral efficacy of topical SPL7013 in rabbit ocular models. In a tolerability study, rabbits [...] Read more.
There is no approved antiviral therapy for adenovirus (HAdV) ocular infections. Astodrimer sodium (SPL7013) is a polyanionic dendrimer with antiviral activity. The current study evaluated the ocular tolerability and anti-adenoviral efficacy of topical SPL7013 in rabbit ocular models. In a tolerability study, rabbits were treated with 3% SPL7013, vehicle, or 0.5% cidofovir. Their eyes were graded using the Draize scale. In antiviral efficacy studies, HAdV5 inoculated eyes were treated with 3% SPL7013, vehicle, or 0.5% cidofovir. Eyes were cultured for the virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. Viral titers were determined. There were no differences in Draize scores between 3% SPL7013 and vehicle on any day. Cidofovir produced significantly higher Draize scores on day 12 than SPL7013 and vehicle. The 3% SPL7013 and 0.5% cidofovir significantly reduced daily viral titers and positive cultures per total compared with vehicle on several different days. The 3% SPL7013 and 0.5% cidofovir significantly reduced the duration of HAdV5 shedding compared to vehicle. The 3% SPL7013 demonstrated significantly more antiviral activity compared with vehicle in the Ad5/NZW rabbit ocular model. The 3% SPL7013 induced “minimal” to “practically non-irritating” Draize scores in the ocular tolerability study. Further development of astodrimer sodium as a topical antiviral therapy for adenoviral ocular infections is indicated. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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18 pages, 3094 KiB  
Article
Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus
by Olivier Terrier, Sébastien Dilly, Andrés Pizzorno, Dominika Chalupska, Jana Humpolickova, Evžen Bouřa, Francis Berenbaum, Stéphane Quideau, Bruno Lina, Bruno Fève, Frédéric Adnet, Michèle Sabbah, Manuel Rosa-Calatrava, Vincent Maréchal, Julien Henri and Anny Slama-Schwok
Molecules 2021, 26(9), 2593; https://doi.org/10.3390/molecules26092593 - 29 Apr 2021
Cited by 32 | Viewed by 20950
Abstract
There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could [...] Read more.
There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could be a strategy to impede viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that was previously demonstrated to be active against Influenza A virus, were evaluated against SARS-CoV-2. Intrinsic fluorescence spectroscopy, fluorescence anisotropy, and dynamic light scattering assays demonstrated naproxen binding to the nucleoprotein of SARS-Cov-2 as predicted by molecular modeling. Naproxen impeded recombinant N oligomerization and inhibited viral replication in infected cells. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage. No inhibition of viral replication was observed with paracetamol or the COX-2 inhibitor celecoxib. Thus, among the NSAID tested, only naproxen combined antiviral and anti-inflammatory properties. Naproxen addition to the standard of care could be beneficial in a clinical setting, as tested in an ongoing clinical study. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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17 pages, 1564 KiB  
Article
Synthesis and Antiviral Activity of Camphene Derivatives against Different Types of Viruses
by Anastasiya S. Sokolova, Valentina P. Putilova, Olga I. Yarovaya, Anastasiya V. Zybkina, Ekaterina D. Mordvinova, Anna V. Zaykovskaya, Dmitriy N. Shcherbakov, Iana R. Orshanskaya, Ekaterina O. Sinegubova, Iana L. Esaulkova, Sophia S. Borisevich, Nikolay I. Bormotov, Larisa N. Shishkina, Vladimir V. Zarubaev, Oleg V. Pyankov, Rinat A. Maksyutov and Nariman F. Salakhutdinov
Molecules 2021, 26(8), 2235; https://doi.org/10.3390/molecules26082235 - 13 Apr 2021
Cited by 32 | Viewed by 4387
Abstract
To date, the ‘one bug-one drug’ approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral infections that turn out to be pathogenic for humans. Evidently, there is an urgent [...] Read more.
To date, the ‘one bug-one drug’ approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral infections that turn out to be pathogenic for humans. Evidently, there is an urgent need for new strategies to develop efficient antiviral agents with broad-spectrum activities. In this paper, we identified camphene derivatives that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses, including influenza virus A/PR/8/34 (H1N1), Ebola virus (EBOV), and the Hantaan virus. The lead-compound 2a, with pyrrolidine cycle in its structure, displayed antiviral activity against influenza virus (IC50 = 45.3 µM), Ebola pseudotype viruses (IC50 = 0.12 µM), and authentic EBOV (IC50 = 18.3 µM), as well as against pseudoviruses with Hantaan virus Gn-Gc glycoprotein (IC50 = 9.1 µM). The results of antiviral activity studies using pseudotype viruses and molecular modeling suggest that surface proteins of the viruses required for the fusion process between viral and cellular membranes are the likely target of compound 2a. The key structural fragments responsible for efficient binding are the bicyclic natural framework and the nitrogen atom. These data encourage us to conduct further investigations using bicyclic monoterpenoids as a scaffold for the rational design of membrane-fusion targeting inhibitors. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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Review

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14 pages, 1711 KiB  
Review
Photosensitizing Antivirals
by Kseniya A. Mariewskaya, Anton P. Tyurin, Alexey A. Chistov, Vladimir A. Korshun, Vera A. Alferova and Alexey V. Ustinov
Molecules 2021, 26(13), 3971; https://doi.org/10.3390/molecules26133971 - 29 Jun 2021
Cited by 22 | Viewed by 3703
Abstract
Antiviral action of various photosensitizers is already summarized in several comprehensive reviews, and various mechanisms have been proposed for it. However, a critical consideration of the matter of the area is complicated, since the exact mechanisms are very difficult to explore and clarify, [...] Read more.
Antiviral action of various photosensitizers is already summarized in several comprehensive reviews, and various mechanisms have been proposed for it. However, a critical consideration of the matter of the area is complicated, since the exact mechanisms are very difficult to explore and clarify, and most publications are of an empirical and “phenomenological” nature, reporting a dependence of the antiviral action on illumination, or a correlation of activity with the photophysical properties of the substances. Of particular interest is substance-assisted photogeneration of highly reactive singlet oxygen (1O2). The damaging action of 1O2 on the lipids of the viral envelope can probably lead to a loss of the ability of the lipid bilayer of enveloped viruses to fuse with the lipid membrane of the host cell. Thus, lipid bilayer-affine 1O2 photosensitizers have prospects as broad-spectrum antivirals against enveloped viruses. In this short review, we want to point out the main types of antiviral photosensitizers with potential affinity to the lipid bilayer and summarize the data on new compounds over the past three years. Further understanding of the data in the field will spur a targeted search for substances with antiviral activity against enveloped viruses among photosensitizers able to bind to the lipid membranes. Full article
(This article belongs to the Special Issue Recent Advances in Antiviral Agents)
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