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Antiviral Agents and Antiviral Defense

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 15640

Special Issue Editor


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Guest Editor
Department for Bioinformatics, Institute of Biomedical Chemistry, 107076 Moscow, Russia
Interests: new heterocycles; bioinformatics; chemoinformatics; QSAR; Transcriptomics; virus-host interactions; virology; HIV

Special Issue Information

Dear Colleagues,

Viral infections are important for humanity because they spread across the human population rapidly and may cause serious consequences for human health. Experimental and computational methods that aim at the development of strategies to combat viral infections are in high demand. The analysis of virus–host interactions is rather helpful for the search of molecular mechanisms, pathways and host proteins that can be targeted by drugs to block viral entry or decrease the intensity of symptoms caused by viral infections. The search for novel antiviral agents is of great importance for combatting viral infections. Viral drug-resistance analysis can help optimize antiviral therapy.

This Special Issue of IJMS welcomes the submission of comprehensive reviews and original research papers that are directed at experimental, computational, and combined methods and their applications for the analysis of molecular mechanisms; the search for potential host targets and novel potential antiviral agents and vaccines; and for the prediction of viral drug resistance. 

Dr. Olga A. Tarasova
Guest Editor

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Keywords

  • viral infections
  • viruses
  • virus–host interactions
  • antiviral defense
  • antiviral agents
  • drug–target interactions
  • signal pathways
  • viral drug resistance

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Published Papers (8 papers)

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Editorial

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4 pages, 211 KiB  
Editorial
Current Perspectives in Antiviral Research
by Olga A. Tarasova
Int. J. Mol. Sci. 2023, 24(19), 14555; https://doi.org/10.3390/ijms241914555 - 26 Sep 2023
Viewed by 1319
Abstract
Studies on virus–host interactions are of high significance for a number of reasons [...] Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)

Research

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14 pages, 3690 KiB  
Article
Nucleoside Reverse Transcriptase Inhibitors Are the Major Class of HIV Antiretroviral Therapeutics That Induce Neuropathic Pain in Mice
by Keegan Bush, Yogesh Wairkar and Shao-Jun Tang
Int. J. Mol. Sci. 2024, 25(16), 9059; https://doi.org/10.3390/ijms25169059 - 21 Aug 2024
Cited by 2 | Viewed by 1038
Abstract
The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications [...] Read more.
The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to a decreased quality of life, some of the most significant of which are neuropathic pain and the development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured the development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptase inhibitors (NRTIs), not other types of antiretrovirals such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote the development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate the design of less toxic forms of these drugs and/or potential mitigation strategies. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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15 pages, 2742 KiB  
Article
Knockdown of DJ-1 Resulted in a Coordinated Activation of the Innate Immune Antiviral Response in HEK293 Cell Line
by Keren Zohar and Michal Linial
Int. J. Mol. Sci. 2024, 25(14), 7550; https://doi.org/10.3390/ijms25147550 - 10 Jul 2024
Viewed by 1539
Abstract
PARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we showed that [...] Read more.
PARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we showed that cell lines vary based on their antioxidation potential under basal conditions. The transcriptome of HEK293 cells was tested following knockdown (KD) of DJ-1 using siRNAs, which reduced the DJ-1 transcripts to only 12% of the original level. We compared the expression levels of 14k protein-coding transcripts and 4.2k non-coding RNAs relative to cells treated with non-specific siRNAs. Among the coding genes, approximately 200 upregulated differentially expressed genes (DEGs) signified a coordinated antiviral innate immune response. Most genes were associated with the regulation of type 1 interferons (IFN) and the induction of inflammatory cytokines. About a quarter of these genes were also induced in cells treated with non-specific siRNAs that were used as a negative control. Beyond the antiviral-like response, 114 genes were specific to the KD of DJ-1 with enrichment in RNA metabolism and mitochondrial functions. A smaller set of downregulated genes (58 genes) was associated with dysregulation in membrane structure, cell viability, and mitophagy. We propose that the KD DJ-1 perturbation diminishes the protective potency against oxidative stress. Thus, it renders the cells labile and responsive to the dsRNA signal by activating a large number of genes, many of which drive apoptosis, cell death, and inflammatory signatures. The KD of DJ-1 highlights its potency in regulating genes associated with antiviral responses, RNA metabolism, and mitochondrial functions, apparently through alteration in STAT activity and downstream signaling. Given that DJ-1 also acts as an oncogene in metastatic cancers, targeting DJ-1 could be a promising therapeutic strategy where manipulation of the DJ-1 level may reduce cancer cell viability and enhance the efficacy of cancer treatments. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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21 pages, 5924 KiB  
Article
Dual Effects of 3-epi-betulin from Daphniphyllum glaucescens in Suppressing SARS-CoV-2-Induced Inflammation and Inhibiting Virus Entry
by Yung-Ju Yeh, Tai-Ling Chao, Yu-Jen Chang, Sui-Yuan Chang, Chih-Hao Lu, Chih-Hua Chao, Wen-Chi Su, Ching-Ping Tseng, Michael M.C. Lai and Ju-Chien Cheng
Int. J. Mol. Sci. 2023, 24(23), 17040; https://doi.org/10.3390/ijms242317040 - 1 Dec 2023
Cited by 2 | Viewed by 2117
Abstract
The continuous emergence of SARS-CoV-2 variants has led to a protracted global COVID-19 pandemic with significant impacts on public health and global economy. While there are currently available SARS-CoV-2 vaccines and therapeutics, most of the FDA-approved antiviral agents directly target viral proteins. However, [...] Read more.
The continuous emergence of SARS-CoV-2 variants has led to a protracted global COVID-19 pandemic with significant impacts on public health and global economy. While there are currently available SARS-CoV-2 vaccines and therapeutics, most of the FDA-approved antiviral agents directly target viral proteins. However, inflammation is the initial immune pathogenesis induced by SARS-CoV-2 infection, there is still a need to find additional agents that can control the virus in the early stages of infection to alleviate disease progression for the next pandemic. Here, we find that both the spike protein and its receptor CD147 are crucial for inducing inflammation by SARS-CoV-2 in THP-1 monocytic cells. Moreover, we find that 3-epi-betulin, isolated from Daphniphyllum glaucescens, reduces the level of proinflammatory cytokines induced by SARS-CoV-2, consequently resulting in a decreased viral RNA accumulation and plaque formation. In addition, 3-epi-betulin displays a broad-spectrum inhibition of entry of SARS-CoV-2 pseudoviruses, including Alpha (B.1.1.7), Eplison (B.1.429), Gamma (P1), Delta (B.1.617.2) and Omicron (BA.1). Moreover, 3-epi-betulin potently inhibits SARS-CoV-2 infection with an EC50 of <20 μM in Calu-3 lung epithelial cells. Bioinformatic analysis reveals the chemical interaction between the 3-epi-betulin and the spike protein, along with the critical amino acid residues in the spike protein that contribute to the inhibitory activity of 3-epi-betulin against virus entry. Taken together, our results suggest that 3-epi-betulin exhibits dual effect: it reduces SARS-CoV-2-induced inflammation and inhibits virus entry, positioning it as a potential antiviral agent against SARS-CoV-2. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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14 pages, 3391 KiB  
Article
Non-Steroidal Estrogens Inhibit Influenza Virus by Interacting with Hemagglutinin and Preventing Viral Fusion
by Elisa Franzi, Gregory Mathez, Soraya Dinant, Charlotte Deloizy, Laurent Kaiser, Caroline Tapparel, Ronan Le Goffic and Valeria Cagno
Int. J. Mol. Sci. 2023, 24(20), 15382; https://doi.org/10.3390/ijms242015382 - 19 Oct 2023
Viewed by 2089
Abstract
Influenza virus is one of the main causes of respiratory infections worldwide. Despite the availability of seasonal vaccines and antivirals, influenza virus infections cause an important health and economic burden. Therefore, the need to identify alternative antiviral strategies persists. In this study, we [...] Read more.
Influenza virus is one of the main causes of respiratory infections worldwide. Despite the availability of seasonal vaccines and antivirals, influenza virus infections cause an important health and economic burden. Therefore, the need to identify alternative antiviral strategies persists. In this study, we identified non-steroidal estrogens as potent inhibitors of influenza virus due to their interaction with the hemagglutinin protein, preventing viral entry. This activity is maintained in vitro, ex vivo, and in vivo. Therefore, we found a new domain to target on the hemagglutinin and a class of compounds that could be further optimized for influenza treatment. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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18 pages, 3555 KiB  
Article
A Novel Time-Resolved Fluorescence Resonance Energy Transfer Assay for the Discovery of Small-Molecule Inhibitors of HIV-1 Tat-Regulated Transcription
by Young Hyun Shin, Dong-Eun Kim, Kyung Lee Yu, Chul Min Park, Hong Gi Kim, Kyung-Chang Kim, Songmee Bae and Cheol-Hee Yoon
Int. J. Mol. Sci. 2023, 24(11), 9139; https://doi.org/10.3390/ijms24119139 - 23 May 2023
Cited by 4 | Viewed by 2379
Abstract
Human immunodeficiency virus-1 (HIV-1) transactivator (Tat)-mediated transcription is essential for HIV-1 replication. It is determined by the interaction between Tat and transactivation response (TAR) RNA, a highly conserved process representing a prominent therapeutic target against HIV-1 replication. However, owing to the limitations of [...] Read more.
Human immunodeficiency virus-1 (HIV-1) transactivator (Tat)-mediated transcription is essential for HIV-1 replication. It is determined by the interaction between Tat and transactivation response (TAR) RNA, a highly conserved process representing a prominent therapeutic target against HIV-1 replication. However, owing to the limitations of current high-throughput screening (HTS) assays, no drug that disrupts the Tat-TAR RNA interaction has been uncovered yet. We designed a homogenous (mix-and-read) time-resolved fluorescence resonance energy transfer (TR-FRET) assay using europium cryptate as a fluorescence donor. It was optimized by evaluating different probing systems for Tat-derived peptides or TAR RNA. The specificity of the optimal assay was validated by mutants of the Tat-derived peptides and TAR RNA fragment, individually and by competitive inhibition with known TAR RNA-binding peptides. The assay generated a constant Tat-TAR RNA interaction signal, discriminating the compounds that disrupted the interaction. Combined with a functional assay, the TR-FRET assay identified two small molecules (460-G06 and 463-H08) capable of inhibiting Tat activity and HIV-1 infection from a large-scale compound library. The simplicity, ease of operation, and rapidity of our assay render it suitable for HTS to identify Tat-TAR RNA interaction inhibitors. The identified compounds may also act as potent molecular scaffolds for developing a new HIV-1 drug class. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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Review

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20 pages, 640 KiB  
Review
Viral Factors in Modulation of Host Immune Response: A Route to Novel Antiviral Agents and New Therapeutic Approaches
by Olga Tarasova, Anthi Petrou, Sergey M. Ivanov, Athina Geronikaki and Vladimir Poroikov
Int. J. Mol. Sci. 2024, 25(17), 9408; https://doi.org/10.3390/ijms25179408 - 29 Aug 2024
Cited by 3 | Viewed by 1976
Abstract
Viruses utilize host cells at all stages of their life cycle, from the transcription of genes and translation of viral proteins to the release of viral copies. The human immune system counteracts viruses through a variety of complex mechanisms, including both innate and [...] Read more.
Viruses utilize host cells at all stages of their life cycle, from the transcription of genes and translation of viral proteins to the release of viral copies. The human immune system counteracts viruses through a variety of complex mechanisms, including both innate and adaptive components. Viruses have an ability to evade different components of the immune system and affect them, leading to disruption. This review covers contemporary knowledge about the virus-induced complex interplay of molecular interactions, including regulation of transcription and translation in host cells resulting in the modulation of immune system functions. Thorough investigation of molecular mechanisms and signaling pathways that are involved in modulating of host immune response to viral infections can help to develop novel approaches for antiviral therapy. In this review, we consider new therapeutic approaches for antiviral treatment. Modern therapeutic strategies for the treatment and cure of human immunodeficiency virus (HIV) are considered in detail because HIV is a unique example of a virus that leads to host T lymphocyte deregulation and significant modulation of the host immune response. Furthermore, peculiarities of some promising novel agents for the treatment of various viral infections are described. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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16 pages, 1337 KiB  
Review
Suppression of Innate Immunity by the Hepatitis C Virus (HCV): Revisiting the Specificity of Host–Virus Interactive Pathways
by Sailen Barik
Int. J. Mol. Sci. 2023, 24(22), 16100; https://doi.org/10.3390/ijms242216100 - 8 Nov 2023
Cited by 5 | Viewed by 2278
Abstract
The hepatitis C virus (HCV) is a major causative agent of hepatitis that may also lead to liver cancer and lymphomas. Chronic hepatitis C affects an estimated 2.4 million people in the USA alone. As the sole member of the genus Hepacivirus within [...] Read more.
The hepatitis C virus (HCV) is a major causative agent of hepatitis that may also lead to liver cancer and lymphomas. Chronic hepatitis C affects an estimated 2.4 million people in the USA alone. As the sole member of the genus Hepacivirus within the Flaviviridae family, HCV encodes a single-stranded positive-sense RNA genome that is translated into a single large polypeptide, which is then proteolytically processed to yield the individual viral proteins, all of which are necessary for optimal viral infection. However, cellular innate immunity, such as type-I interferon (IFN), promptly thwarts the replication of viruses and other pathogens, which forms the basis of the use of conjugated IFN-alpha in chronic hepatitis C management. As a countermeasure, HCV suppresses this form of immunity by enlisting diverse gene products, such as HCV protease(s), whose primary role is to process the large viral polyprotein into individual proteins of specific function. The exact number of HCV immune suppressors and the specificity and molecular mechanism of their action have remained unclear. Nonetheless, the evasion of host immunity promotes HCV pathogenesis, chronic infection, and carcinogenesis. Here, the known and putative HCV-encoded suppressors of innate immunity have been reviewed and analyzed, with a predominant emphasis on the molecular mechanisms. Clinically, the knowledge should aid in rational interventions and the management of HCV infection, particularly in chronic hepatitis. Full article
(This article belongs to the Special Issue Antiviral Agents and Antiviral Defense)
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