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Viruses
Special Issues
Innovative Drug Discovery for Emerging Viral Diseases
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Innovative Drug Discovery for Emerging Viral Diseases

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 4773

Special Issue Editors

Dr. Chaoping Chen

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA
Interests: HIV-1 protease autoprocessing mechanism and drug discovery
Dr. Andreas Jekle

E-Mail Website
Guest Editor
Aligos Therapeutics, Inc., South San Francisco, CA 94080, USA
Interests: antiviral drug discovery; HBV; SARS-CoV-2

Special Issue Information

Dear Colleagues,

The COVID-19 pandemic has highlighted the sobering potential of certain members of several viral families to cause unexpected outbreaks with high-burden diseases that might disrupt healthcare systems and devastate economies in the future. Currently, no highly active direct-acting antiviral drugs are available for several virus families such as the togaviridae (chikungunya virus), hantaviridae (Hantavirus) or the filoviridae (Ebolavirus, Marburg Virus). Additionally, the rapid development of drug resistance, exemplified by all classes of HIV antiretrovirals, presents extra hurdles to disease control. Therefore, proactive and innovative antiviral drug discovery is urgently needed to ensure preparedness to mitigate the threat caused by these viral pathogens.

Antivirals have traditionally been developed by directly targeting essential viral components through structure-based rational design. Other strategies have been less exploited, such as function-based high-throughput screening (HTS) either in vitro/vivo or in silicon, targeting host factors that are critical for virus replication but dispensable for the host, and potentiation of immune responses (i.e., immunomodulators). This Special Issue of Viruses seeks to attract top-level publications covering conventional or innovative designs, developments and validations of antivirals in relation to emerging/re-emerging RNA viral pathogens. We invite you to share your most insightful research, reviews and hypotheses on these important topics.

Dr. Chaoping Chen
Dr. Andreas Jekle
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

  • antivirals
  • drug discovery
  • high-throughput screen
  • SARS-CoV-2
  • Influenza virus
  • RSV
  • Zika
  • Ebola Virus
  • chikungunya virus
  • emerging/re-emerging RNA viral pathogens
  • host-directed therapies
  • immunomodulator

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Published Papers (4 papers)

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Research

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19 pages, 8954 KiB  
Article
N-Acetylcysteine Inhibits Coxsackievirus B3 Replication by Downregulating Eukaryotic Translation Elongation Factor 1 Alpha 1
by Yao Wang, Tian Luan, Lixin Wang, Danxiang Feng, Yanyan Dong, Siwei Li, Hong Yang, Yang Chen, Yanru Fei, Lexun Lin, Jiahui Pan, Zhaohua Zhong and Wenran Zhao
Viruses 2024, 16(9), 1503; https://doi.org/10.3390/v16091503 - 23 Sep 2024
Viewed by 770
Abstract
Group B Coxsackieviruses (CVB) are one of the causative pathogens of myocarditis, which may progress to cardiomyopathy. The pathogenesis of CVB is not fully understood, and effective antiviral therapy is not available. N-acetylcysteine (NAC), the classic antioxidant, has been used in clinical practice [...] Read more.
Group B Coxsackieviruses (CVB) are one of the causative pathogens of myocarditis, which may progress to cardiomyopathy. The pathogenesis of CVB is not fully understood, and effective antiviral therapy is not available. N-acetylcysteine (NAC), the classic antioxidant, has been used in clinical practice for several decades to treat various medical conditions. In this study, the anti-CVB effect of NAC was investigated. We show that NAC dramatically suppressed viral replication and alleviated cardiac injury induced by CVB3. To further study the antiviral mechanism of NAC, RNA-sequencing was performed for CVB3-infected cells with NAC treatment. We found that eukaryotic elongation factor 1 alpha 1 (EEF1A1) is one of the most upregulated genes in CVB3-infected cells. However, EEF1A2, the highly homologous isoform of EEF1A1, remains unchanged. EEF1A1 expression was significantly suppressed by NAC treatment in CVB3-infected cells, while EEF1A2 was not affected. eEF1A1 knockdown significantly inhibited CVB3 replication, implicating that eEF1A1 facilitates viral replication. Importantly, we show that eEF1A1, which was not expressed in the myocardia of newborn mice, was significantly upregulated by CVB3 infection. NAC markedly downregulated the expression of eEF1A1 but not eEF1A2 in the myocardia of CVB3-infected mice. Furthermore, NAC accelerated eEF1A1 degradation by promoting autophagy in CVB3-infected cells. We show that p62, one of the critical adaptors of autophagic targets, interacts with eEF1A1 and was downregulated in CVB3-infected cells upon NAC treatment. Taken together, this study demonstrated that NAC shows a potent anti-CVB effect through the downregulation of eEF1A1. Full article
(This article belongs to the Special Issue Innovative Drug Discovery for Emerging Viral Diseases)
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19 pages, 2551 KiB  
Article
Assay Development and Validation for Innovative Antiviral Development Targeting the N-Terminal Autoprocessing of SARS-CoV-2 Main Protease Precursors
by Liangqun Huang, Megan Gish, James Boehlke, Ryan H. Jeep and Chaoping Chen
Viruses 2024, 16(8), 1218; https://doi.org/10.3390/v16081218 - 29 Jul 2024
Viewed by 719
Abstract
The SARS-CoV-2 main protease (Mpro) is initially synthesized as part of polyprotein precursors that undergo autoproteolysis to release the free mature Mpro. To investigate the autoprocessing mechanism in transfected mammalian cells, we examined several fusion precursors, with the mature [...] Read more.
The SARS-CoV-2 main protease (Mpro) is initially synthesized as part of polyprotein precursors that undergo autoproteolysis to release the free mature Mpro. To investigate the autoprocessing mechanism in transfected mammalian cells, we examined several fusion precursors, with the mature SARS-CoV-2 Mpro along with the flanking amino acids (to keep the native substrate sequences) sandwiched between different tags. Our analyses revealed differential proteolysis kinetics at the N- and C-terminal cleavage sites. Particularly, N-terminal processing is differentially influenced by various upstream fusion tags (GST, sGST, CD63, and Nsp4) and amino acid variations at the N-terminal P1 position, suggesting that precursor catalysis is flexible and subject to complex regulation. Mutating Q to E at the N-terminal P1 position altered both precursor catalysis and the properties of the released Mpro. Interestingly, the wild-type precursors exhibited different enzymatic activities compared to those of the released Mpro, displaying much lower susceptibility to known inhibitors targeting the mature form. These findings suggest the precursors as alternative targets for antiviral development. Accordingly, we developed and validated a high-throughput screening (HTS)-compatible platform for functional screening of compounds targeting either the N-terminal processing of the SARS-CoV-2 Mpro precursor autoprocessing or the released mature Mpro through different mechanisms of action. Full article
(This article belongs to the Special Issue Innovative Drug Discovery for Emerging Viral Diseases)
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21 pages, 7637 KiB  
Article
The Dual-Targeted Fusion Inhibitor Clofazimine Binds to the S2 Segment of the SARS-CoV-2 Spike Protein
by Matthew R. Freidel, Pratiti A. Vakhariya, Shalinder K. Sardarni and Roger S. Armen
Viruses 2024, 16(4), 640; https://doi.org/10.3390/v16040640 - 20 Apr 2024
Viewed by 1479
Abstract
Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed [...] Read more.
Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 Spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and its derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest-quality SPR data for binding with S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results related to molecular docking and modeling of the structure–activity relationship (SAR) of a newly reported series of Clofazimine derivatives support the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure–sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronaviruses such as SARS-CoV, MERS, hCoV-229E, and hCoV-OC43. Full article
(This article belongs to the Special Issue Innovative Drug Discovery for Emerging Viral Diseases)
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Review

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16 pages, 6555 KiB  
Review
Research Progress on Spike-Dependent SARS-CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike
by Matthew R. Freidel and Roger S. Armen
Viruses 2024, 16(5), 712; https://doi.org/10.3390/v16050712 - 30 Apr 2024
Viewed by 1389
Abstract
Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike [...] Read more.
Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small-molecule binding sites on Spike, it was unclear what the specific mechanism of action was or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor-binding domain (RBD) or N-terminal domain (NTD) and disrupt the S1 receptor-binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most substitutions to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved, with only a few observed substitutions in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over recent VOC mutant strains and/or greater broad-spectrum antiviral activity for other more distantly related coronaviruses. Full article
(This article belongs to the Special Issue Innovative Drug Discovery for Emerging Viral Diseases)
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