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Viruses
Special Issues
Innovative Inhibitors against Viral Targets
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Innovative Inhibitors against Viral Targets

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 July 2023) | Viewed by 13079

Special Issue Editors

Dr. Angela Corona

E-Mail Website
Guest Editor
Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy
Interests: antivirals; retroviruses; filoviruses; host–pathogen interactions
Dr. St Patrick Reid

E-Mail Website
Guest Editor
Department of Pathology and Microbiology, College of Medicine and University of Nebraska Medical Center (UNMC), Omaha, NE, USA
Interests: host-pathogen interactions; alphaviruses; filoviruses; innate immunity; host-based antivirals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses are pathogens prone to rapid host adaptation and to the selection of drug-resistant variants. The current COVID-19 pandemic reminded us of the urgent need for antiviral drugs to face present and future outbreaks. Additionally, constant effort is needed to identify new viral inhibitors for both acute and persistent viral infections. Viral-encoded proteins that cannot be complemented by host functions are validated targets to be exploited, especially if they exhibit a high level of conservation upon selective pressure.

This Special Issue of the journal Viruses on “Innovative Inhibitors against Viral Targets” is focused on the solutions being explored to block viral-encoded targets. We welcome submissions including but not limited to:

  • Modulation of the antiviral innate immune response—a target for the development of novel pan-viral therapeutic strategies;
  • Inhibitors of viral enzymes and functions;
  • Natural products (derivatives) as inhibitors.

Dr. Angela Corona
Dr. St Patrick Reid
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

  • viral proteins
  • virus replication
  • antivirals
  • viral targets
  • molecular virology
  • target-based drug design
  • host-pathogen interaction

Published Papers (7 papers)

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Research

Jump to: Review, Other

19 pages, 4526 KiB  
Article
Epigallocatechin Gallate-Modified Silver Nanoparticles Show Antiviral Activity against Herpes Simplex Type 1 and 2
by Malgorzata Krzyzowska, Martyna Janicka, Marcin Chodkowski, Magdalena Patrycy, Oliwia Obuch-Woszczatyńska, Emilia Tomaszewska, Katarzyna Ranoszek-Soliwoda, Grzegorz Celichowski and Jaroslaw Grobelny
Viruses 2023, 15(10), 2024; https://doi.org/10.3390/v15102024 - 29 Sep 2023
Cited by 1 | Viewed by 1230
Abstract
(1) Background: Epigallocatechin gallate (EGCG) has been recognized as a flavonoid showing antiviral activity against various types of DNA and RNA viruses. In this work, we tested if EGCG-modified silver nanoparticles (EGCG-AgNPs) can become novel microbicides with additional adjuvant properties to treat herpes [...] Read more.
(1) Background: Epigallocatechin gallate (EGCG) has been recognized as a flavonoid showing antiviral activity against various types of DNA and RNA viruses. In this work, we tested if EGCG-modified silver nanoparticles (EGCG-AgNPs) can become novel microbicides with additional adjuvant properties to treat herpes infections. (2) Methods: The anti-HSV and cytotoxic activities of EGCG-AgNPs were tested in human HaCaT and VK-2-E6/E7 keratinocytes. HSV-1/2 titers and immune responses after treatment with EGCG-AgNPs were tested in murine models of intranasal HSV-1 infection and genital HSV-2 infection. (3) Results: EGCG-AgNPs inhibited attachment and entry of HSV-1 and HSV-2 in human HaCaT and VK-2-E6/E7 keratinocytes much better than EGCG at the same concentration. Infected mice treated intranasally (HSV-1) or intravaginally (HSV-2) with EGCG-AgNPs showed lower virus titers in comparison to treatment with EGCG alone. After EGCG-AgNPs treatment, mucosal tissues showed a significant infiltration in dendritic cells and monocytes in comparison to NaCl-treated group, followed by significantly better infiltration of CD8+ T cells, NK cells and increased expression of IFN-α, IFN-γ, CXCL9 and CXCL10. (4) Conclusions: Our findings show that EGCG-AgNPs can become an effective novel antiviral microbicide with adjuvant properties to be applied upon the mucosal tissues. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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18 pages, 5514 KiB  
Article
Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication
by Abhishek Asthana, Angela Corona, Woo-Jin Shin, Mi-Jeong Kwak, Christina Gaughan, Enzo Tramontano, Jae U. Jung, Rainer Schobert, Babal Kant Jha, Robert H. Silverman and Bernhard Biersack
Viruses 2023, 15(7), 1539; https://doi.org/10.3390/v15071539 - 13 Jul 2023
Cited by 2 | Viewed by 1691
Abstract
Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are [...] Read more.
Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3′-to-5′ exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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12 pages, 2550 KiB  
Article
Novel Tetrahydroisoquinoline-Based Heterocyclic Compounds Efficiently Inhibit SARS-CoV-2 Infection In Vitro
by Xi Wang, Nikola T. Burdzhiev, Hengrui Hu, Yufeng Li, Jiang Li, Vesela V. Lozanova, Meglena I. Kandinska and Manli Wang
Viruses 2023, 15(2), 502; https://doi.org/10.3390/v15020502 - 11 Feb 2023
Viewed by 1356
Abstract
The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication [...] Read more.
The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro. In this study, we discussed the syntheses of two novel heterocylic compounds: tert-butyl rel-4-(((3R,4S)-3-(1H-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (trans-1) and rel-(3R,4S)-3-(1H-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (trans-2), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans-1 showed higher anti-SARS-CoV-2 activity than trans-2, with a half maximal effective concentration (EC50) of 3.15 μM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans-1 efficiently inhibited viral replication (EC50 = 2.78 μM; SI: > 71.94) and performed better than CQ (EC50 = 44.90 μM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans-1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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20 pages, 6416 KiB  
Article
Exploration of Microbially Derived Natural Compounds against Monkeypox Virus as Viral Core Cysteine Proteinase Inhibitors
by Amit Dubey, Maha M. Alawi, Thamir A. Alandijany, Isra M. Alsaady, Sarah A. Altwaim, Amaresh Kumar Sahoo, Vivek Dhar Dwivedi and Esam Ibraheem Azhar
Viruses 2023, 15(1), 251; https://doi.org/10.3390/v15010251 - 16 Jan 2023
Cited by 18 | Viewed by 2466
Abstract
Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus and the Poxviridae family, which instigated a rising epidemic called monkeypox disease. Proteinases are majorly engaged in viral propagation by catalyzing the cleavage of precursor polyproteins. Therefore, proteinase is essential for monkeypox and [...] Read more.
Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus and the Poxviridae family, which instigated a rising epidemic called monkeypox disease. Proteinases are majorly engaged in viral propagation by catalyzing the cleavage of precursor polyproteins. Therefore, proteinase is essential for monkeypox and a critical drug target. In this study, high-throughput virtual screening (HTVS) and molecular dynamics simulation were applied to detect the potential natural compounds against the proteinase of the monkeypox virus. Here, 32,552 natural products were screened, and the top five compounds were selected after implementing the HTVS and molecular docking protocols in series. Gallicynoic Acid F showed the minimum binding score of −10.56 kcal/mole in the extra precision scoring method, which reflected the highest binding with the protein. The top five compounds showed binding scores ≤−8.98 kcal/mole. These compound complexes were tested under 100 ns molecular dynamics simulation, and Vaccinol M showed the most stable and consistent RMSD trend in the range of 2 Å to 3 Å. Later, MM/GBSA binding free energy and principal component analysis were performed on the top five compounds to validate the stability of selected compound complexes. Moreover, the ligands Gallicynoic Acid F and H2-Erythro-Neopterin showed the lowest binding free energies of −61.42 kcal/mol and −61.09 kcal/mol, respectively. Compared to the native ligand TTP-6171 (ΔGBind = −53.86 kcal/mol), these two compounds showed preferable binding free energy, suggesting inhibitory application against MPXV proteinase. This study proposed natural molecules as a therapeutic solution to control monkeypox disease. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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Review

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31 pages, 5824 KiB  
Review
Current Status and Challenges in Anti-Hepatitis B Virus Agents Based on Inactivation/Inhibition or Elimination of Hepatitis B Virus Covalently Closed Circular DNA
by An-Qi Zhuang, Yan Chen, Shan-Mei Chen, Wen-Cheng Liu, Yao Li, Wen-Jie Zhang and Yi-Hang Wu
Viruses 2023, 15(12), 2315; https://doi.org/10.3390/v15122315 - 25 Nov 2023
Viewed by 1395
Abstract
There has been over half a century since the discovery of hepatitis B virus (HBV) to now, but approximately 300 million patients with chronic hepatitis B (CHB) still live in the world, resulting in about one million deaths every year. Although currently approved [...] Read more.
There has been over half a century since the discovery of hepatitis B virus (HBV) to now, but approximately 300 million patients with chronic hepatitis B (CHB) still live in the world, resulting in about one million deaths every year. Although currently approved antivirals (e.g., nucleoside analogues) are effective at reducing HBV replication, they have almost no impact on the existing HBV covalently closed circular DNA (cccDNA) reservoir. HBV cccDNA is a critical obstacle to the complete elimination of the virus via antiviral therapy. The true cure of HBV infection requires the eradication of viral cccDNA from HBV-infected cells; thus, the development of new agents directly or indirectly targeting HBV cccDNA is urgently needed due to the limitations of current available drugs against HBV infection. In this regard, it is the major focus of current anti-HBV research worldwide via different mechanisms to either inactivate/inhibit (functional cure) or eliminate (complete cure) HBV cccDNA. Therefore, this review discussed and summarized recent advances and challenges in efforts to inactivate/silence or eliminate viral cccDNA using anti-HBV agents from different sources, such as small molecules (including epigenetic drugs) and polypeptides/proteins, and siRNA or gene-editing approaches targeting/attenuating HBV cccDNA via different mechanisms, as well as future directions that may be considered in efforts to truly cure chronic HBV infection. In conclusion, no breakthrough has been made yet in attenuating HBV cccDNA, although a number of candidates have advanced into the phase of clinical trials. Furthermore, the overwhelming majority of the candidates function to indirectly target HBV cccDNA. No outstanding candidate directly targets HBV cccDNA. Relatively speaking, CCC_R08 and nitazoxanide may be some of the most promising agents to clear HBV infection in small molecule compounds. Additionally, CRISPR-Cas9 systems can directly target HBV cccDNA for decay and demonstrate significant anti-HBV activity. Consequently, gene-editing approaches targeting HBV cccDNA may be one of the most promising means to achieve the core goal of anti-HBV therapeutic strategies. In short, more basic studies on HBV infection need to be carried out to overcome these challenges. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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18 pages, 2249 KiB  
Review
Small GTPase—A Key Role in Host Cell for Coronavirus Infection and a Potential Target for Coronavirus Vaccine Adjuvant Discovery
by Wei Hou, Sibei Wang, Heqiong Wu, Linli Xue, Bin Wang, Shouyu Wang and Haidong Wang
Viruses 2022, 14(9), 2044; https://doi.org/10.3390/v14092044 - 14 Sep 2022
Cited by 3 | Viewed by 1855
Abstract
Small GTPases are signaling molecules in regulating key cellular processes (e.g., cell differentiation, proliferation, and motility) as well as subcellular events (e.g., vesicle trafficking), making them key participants, especially in a great array of coronavirus infection processes. In this review, we discuss the [...] Read more.
Small GTPases are signaling molecules in regulating key cellular processes (e.g., cell differentiation, proliferation, and motility) as well as subcellular events (e.g., vesicle trafficking), making them key participants, especially in a great array of coronavirus infection processes. In this review, we discuss the role of small GTPases in the coronavirus life cycle, especially pre-entry, endocytosis, intracellular traffic, replication, and egress from the host cell. Furthermore, we also suggest the molecules that have potent adjuvant activity by targeting small GTPases. These studies provide deep insights and references to understand the pathogenesis of coronavirus as well as to propose the potential of small GTPases as targets for adjuvant development. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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Other

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8 pages, 716 KiB  
Brief Report
Antiviral Activity of Micafungin and Its Derivatives against SARS-CoV-2 RNA Replication
by Shogo Nakajima, Hirofumi Ohashi, Daisuke Akazawa, Shiho Torii, Rigel Suzuki, Takasuke Fukuhara and Koichi Watashi
Viruses 2023, 15(2), 452; https://doi.org/10.3390/v15020452 - 06 Feb 2023
Cited by 3 | Viewed by 2284
Abstract
Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses such as flavivirus, alphavirus, and coronavirus. In this study, we focused on micafungin and its derivatives and analyzed their antiviral activities against severe acute [...] Read more.
Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses such as flavivirus, alphavirus, and coronavirus. In this study, we focused on micafungin and its derivatives and analyzed their antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The micafungin derivatives Mi-2 and Mi-5 showed higher antiviral activity than micafungin, with 50% maximal inhibitory concentration (IC50) of 5.25 and 6.51 µM, respectively (3.8 to 4.7-fold stronger than micafungin) and 50% cytotoxic concentration (CC50) of >64 µM in VeroE6/TMPRSS2 cells. This high anti-SARS-CoV-2 activity was also conserved in human lung epithelial cell-derived Calu-3 cells. Micafungin, Mi-2, and Mi-5 were suggested to inhibit the intracellular virus replication process; additionally, these compounds were active against SARS-CoV-2 variants, including Delta (AY.122, hCoV-19/Japan/TY11-927/2021), Omicron (BA.1.18, hCoV-19/Japan/TY38-873/2021), a variant resistant to remdesivir (R10/E796G C799F), and a variant resistant to casirivimab/imdevimab antibody cocktail (E406W); thus, our results provide basic evidence for the potential use of micafungin derivatives for developing antiviral agents. Full article
(This article belongs to the Special Issue Innovative Inhibitors against Viral Targets)
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