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Antiviral Molecular Mechanisms

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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 (1 July 2023) | Viewed by 39840

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Dr. Graciela Andrei

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Rega Institute, Department of Microbiology, Immunomogy & Transplantation, KU Leuven, Leuven, Belgium
Interests: virology; DNA viruses; antivirals; drug resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of antivirals to combat viral infections is a long process, requiring multidisciplinary approaches. Antiviral drug discovery is mainly focused on two different strategies: targeting the viral cycle or targeting host cell factors. A critical step in antiviral drug discovery includes basic virological research able to identify potential viral or host targets. Analysis of the molecular mechanism of action of antivirals is fundamental for predicting and understanding side-effects, drug interactions, and the emergence of resistance, for increasing the spectrum of activity, and for improving efficacy.

In the past few decades, the world has been confronted with several outbreaks caused by zoonotic viruses, including Ebola, Influenza A (H1N1), SARS, MERS, Zika virus, and SARS-CoV-2 (the cause of the ongoing COVID-19 pandemic), with a tremendous global impact on public health, society, and economy. Thousands of compounds, including newly synthesized molecules, and repurposed drugs are being investigated to fight against (re)emerging viral infections. Although computer simulation is an essential tool to elucidate conformational changes at the molecular level, it needs to be complemented by biological assays. Cell-culture based assays are commonly employed for hit identification and study of the molecular mechanism of action. The use of extensive and appropriate molecular biological assays is fundamental for dissecting in detail the viral replicative cycle, the molecular mechanisms of inhibition by antivirals and the key molecular determinants of antiviral drug resistance, which will help selecting the most promising antivirals for clinical use.

In this Special Issue, we welcome manuscripts that focus on a deep understanding of the molecular details of direct acting antivirals as well as host targeting inhibitors in relation to the virus cycle. This will assist the development of broad-spectrum antivirals (BSAAs), which can inhibit a range of viruses by targeting conserved viral replication processes and/or viral proteins, or alternatively by affecting commonly used host factors necessary for viral multiplication. BSAAs are important not only for the control of emerging and re-emerging diseases but also endemic viral pathogens (e.g., HBV and herpesviruses) that had been infecting and co-evolved with humans for centuries.

Prof. Dr. Graciela Andrei
Guest Editor

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Keywords

direct acting antiviral agents
host-cell targets
broad-spectrum antiviral agents
(re)emerging viral infections
molecular mechanisms of antivirals
molecular mechanisms of drug-resistance

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Published Papers (11 papers)

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Research

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12 pages, 2122 KiB

Open AccessArticle

The Interferon-Induced Protein with Tetratricopeptide Repeats Repress Influenza Virus Infection by Inhibiting Viral RNA Synthesis

by Zhengyu Zhu, Xiaoyun Yang, Chaoqun Huang and Lin Liu

Viruses 2023, 15(7), 1412; https://doi.org/10.3390/v15071412 - 22 Jun 2023

Cited by 2 | Viewed by 2027

Abstract

Influenza A virus (IAV) is an eight-segment negative-sense RNA virus and is subjected to gene recombination between strains to form novel strains, which may lead to influenza pandemics. Seasonal influenza occurs annually and causes great losses in public healthcare. In this study, we examined the role of interferon-induced protein with tetratricopeptide repeats 1 and 2 (IFIT1 and IFIT2) in influenza virus infection. Knockdown of IFIT1 or IFIT2 using a lentiviral shRNA increased viral nucleoprotein (NP) and nonstructural protein 1 (NS1) protein levels, as well as progeny virus production in A/Puerto Rico/8/34 H1N1 (PR/8)-infected lung epithelial A549 cells. Overexpression of IFIT1 or IFIT2 reduced viral NP and NS1 RNA and protein levels in PR/8-infected HEK293 cells. Overexpression of IFIT1 or IFIT2 also inhibited influenza virus infection of various H1N1 strains, including PR/8, A/WSN/1933, A/California/07/2009 and A/Oklahoma/3052/2009, as determined by a viral reporter luciferase assay. Furthermore, knockdown of IFIT1 or IFIT2 increased while overexpression of IFIT1 or IFIT2 decreased viral RNA, complementary RNA, and mRNA levels of NP and NS1, as well as viral polymerase activities. Taken together, our results support that both IFIT1 and -2 have anti-influenza virus activities by inhibiting viral RNA synthesis. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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16 pages, 716 KiB

Open AccessArticle

Tizoxanide Antiviral Activity on Dengue Virus Replication

by Kristie A. Yamamoto, Kevin Blackburn, Michael B. Goshe, Dennis T. Brown, Edimilson Migoswski, Isabele B. Campanhon, Monica F. Moreira, Davis F. Ferreira and Marcia R. Soares

Viruses 2023, 15(3), 696; https://doi.org/10.3390/v15030696 - 7 Mar 2023

Cited by 2 | Viewed by 2556

Abstract

Dengue virus is an important circulating arbovirus in Brazil responsible for high morbidity and mortality worldwide, representing a huge economic and social burden, in addition to affecting public health. In this study, the biological activity, toxicity, and antiviral activity against dengue virus type 2 (DENV-2) of tizoxanide (TIZ) was evaluated in Vero cell culture. TIZ has a broad spectrum of action in inhibiting different pathogens, including bacteria, protozoa, and viruses. Cells were infected for 1 h with DENV-2 and then treated for 24 h with different concentrations of the drug. The quantification of viral production indicated the antiviral activity of TIZ. The protein profiles in infected Vero cells treated and not treated with TIZ were analyzed using the label-free quantitative proteomic approach. TIZ was able to inhibit virus replication mainly intracellularly after DENV-2 penetration and before the complete replication of the viral genome. Additionally, the study of the protein profile of infected not-treated and infected-treated Vero cells showed that TIZ interferes with cellular processes such as intracellular trafficking and vesicle-mediated transport and post-translational modifications when added after infection. Our results also point to the activation of immune response genes that would eventually lead to a decrease of DENV-2 production. TIZ is a promising therapeutic molecule for the treatment of DENV-2 infections. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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20 pages, 3125 KiB

Open AccessArticle

Small-Angle X-ray Scattering (SAXS) Measurements of APOBEC3G Provide Structural Basis for Binding of Single-Stranded DNA and Processivity

by Fareeda M. Barzak, Timothy M. Ryan, Nazanin Mohammadzadeh, Stefan Harjes, Maksim V. Kvach, Harikrishnan M. Kurup, Kurt L. Krause, Linda Chelico, Vyacheslav V. Filichev, Elena Harjes and Geoffrey B. Jameson

Viruses 2022, 14(9), 1974; https://doi.org/10.3390/v14091974 - 6 Sep 2022

Cited by 2 | Viewed by 3541

Abstract

APOBEC3 enzymes are polynucleotide deaminases, converting cytosine to uracil on single-stranded DNA (ssDNA) and RNA as part of the innate immune response against viruses and retrotransposons. APOBEC3G is a two-domain protein that restricts HIV. Although X-ray single-crystal structures of individual catalytic domains of APOBEC3G with ssDNA as well as full-length APOBEC3G have been solved recently, there is little structural information available about ssDNA interaction with the full-length APOBEC3G or any other two-domain APOBEC3. Here, we investigated the solution-state structures of full-length APOBEC3G with and without a 40-mer modified ssDNA by small-angle X-ray scattering (SAXS), using size-exclusion chromatography (SEC) immediately prior to irradiation to effect partial separation of multi-component mixtures. To prevent cytosine deamination, the target 2′-deoxycytidine embedded in 40-mer ssDNA was replaced by 2′-deoxyzebularine, which is known to inhibit APOBEC3A, APOBEC3B and APOBEC3G when incorporated into short ssDNA oligomers. Full-length APOBEC3G without ssDNA comprised multiple multimeric species, of which tetramer was the most scattering species. The structure of the tetramer was elucidated. Dimeric interfaces significantly occlude the DNA-binding interface, whereas the tetrameric interface does not. This explains why dimers completely disappeared, and monomeric protein species became dominant, when ssDNA was added. Data analysis of the monomeric species revealed a full-length APOBEC3G–ssDNA complex that gives insight into the observed “jumping” behavior revealed in studies of enzyme processivity. This solution-state SAXS study provides the first structural model of ssDNA binding both domains of APOBEC3G and provides data to guide further structural and enzymatic work on APOBEC3–ssDNA complexes. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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18 pages, 3604 KiB

Open AccessArticle

Specific Interaction of DARPin with HIV-1 CA_NTD Disturbs the Distribution of Gag, RNA Packaging, and Tetraspanin Remodelling in the Membrane

by Sutpirat Moonmuang, Rawiwan Maniratanachote, Paninee Chetprayoon, Kanokporn Sornsuwan, Weeraya Thongkum, Koollawat Chupradit and Chatchai Tayapiwatana

Viruses 2022, 14(4), 824; https://doi.org/10.3390/v14040824 - 15 Apr 2022

Cited by 2 | Viewed by 2428

Abstract

A designed repeat scaffold protein (Ank^GAG1D4) recognizing the human immunodeficiency virus-1 (HIV-1) capsid (CA) was formerly established with antiviral assembly. Here, we investigated the molecular mechanism of Ank^GAG1D4 function during the late stages of the HIV-1 replication cycle. By applying stimulated emission-depletion (STED) microscopy, Gag polymerisation was interrupted at the plasma membrane. Disturbance of Gag polymerisation triggered Gag accumulation inside producer cells and trapping of the CD81 tetraspanin on the plasma membrane. Moreover, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) experiments were performed to validate the packaging efficiency of RNAs. Our results advocated that Ank^GAG1D4 interfered with the Gag precursor protein from selecting HIV-1 and cellular RNAs for encapsidation into viral particles. These findings convey additional information on the antiviral activity of Ank^GAG1D4 at late stages of the HIV-1 life cycle, which is potential for an alternative anti-HIV molecule. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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19 pages, 7012 KiB

Open AccessArticle

Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation

by Nilottam Rana, Atul Kumar Singh, Mohd Shuaib, Sanjay Gupta, Mahmoud M. Habiballah, Mustfa F. Alkhanani, Shafiul Haque, Mohd Salim Reshi and Shashank Kumar

Viruses 2022, 14(4), 697; https://doi.org/10.3390/v14040697 - 28 Mar 2022

Cited by 18 | Viewed by 3688

Abstract

Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (∆G) in the M46I–saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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Review

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14 pages, 1338 KiB

Open AccessReview

Targeting the Host Mitochondria as a Novel Human Cytomegalovirus Antiviral Strategy

by Lauryn O. Bachman and Kevin J. Zwezdaryk

Viruses 2023, 15(5), 1083; https://doi.org/10.3390/v15051083 - 28 Apr 2023

Cited by 4 | Viewed by 2588

Abstract

Human cytomegalovirus (HCMV) exploits host mitochondrial function to promote viral replication. HCMV gene products have been described to directly interact and alter functional or structural aspects of host mitochondria. Current antivirals against HCMV, such as ganciclovir and letermovir, are designed against viral targets. Concerns with the current antivirals include toxicity and viral resistance. Targeting host mitochondrial function is a promising alternative or complimentary antiviral approach as (1) drugs targeting host mitochondrial function interact with host targets, minimizing viral resistance, and (2) host mitochondrial metabolism plays key roles in HCMV replication. This review describes how HCMV alters mitochondrial function and highlights pharmacological targets that can be exploited for novel antiviral development. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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21 pages, 2870 KiB

Open AccessReview

Cellular Targets of HIV-1 Protease: Just the Tip of the Iceberg?

by Matteo Centazzo, Lara Manganaro and Gualtiero Alvisi

Viruses 2023, 15(3), 712; https://doi.org/10.3390/v15030712 - 9 Mar 2023

Cited by 4 | Viewed by 2979

Abstract

Human immunodeficiency virus 1 (HIV-1) viral protease (PR) is one of the most studied viral enzymes and a crucial antiviral target. Despite its well-characterized role in virion maturation, an increasing body of research is starting to focus on its ability to cleave host cell proteins. Such findings are apparently in contrast with the dogma of HIV-1 PR activity being restricted to the interior of nascent virions and suggest catalytic activity within the host cell environment. Given the limited amount of PR present in the virion at the time of infection, such events mainly occur during late viral gene expression, mediated by newly synthesized Gag-Pol polyprotein precursors, rather than before proviral integration. HIV-1 PR mainly targets proteins involved in three different processes: those involved in translation, those controlling cell survival, and restriction factors responsible for innate/intrinsic antiviral responses. Indeed, by cleaving host cell translation initiation factors, HIV-1 PR can impair cap-dependent translation, thus promoting IRES-mediated translation of late viral transcripts and viral production. By targeting several apoptotic factors, it modulates cell survival, thus promoting immune evasion and viral dissemination. Additionally, HIV-1 PR counteracts restriction factors incorporated in the virion that would otherwise interfere with nascent virus vitality. Thus, HIV-1 PR appears to modulate host cell function at different times and locations during its life cycle, thereby ensuring efficient viral persistency and propagation. However, we are far from having a complete picture of PR-mediated host cell modulation, which is emerging as a field that needs further investigation. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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37 pages, 4522 KiB

Open AccessReview

Molecular Mechanisms of Antiviral Agents against Dengue Virus

by Michelle Felicia Lee, Yuan Seng Wu and Chit Laa Poh

Viruses 2023, 15(3), 705; https://doi.org/10.3390/v15030705 - 8 Mar 2023

Cited by 28 | Viewed by 7332

Abstract

Dengue is a major global health threat causing 390 million dengue infections and 25,000 deaths annually. The lack of efficacy of the licensed Dengvaxia vaccine and the absence of a clinically approved antiviral against dengue virus (DENV) drive the urgent demand for the development of novel anti-DENV therapeutics. Various antiviral agents have been developed and investigated for their anti-DENV activities. This review discusses the mechanisms of action employed by various antiviral agents against DENV. The development of host-directed antivirals targeting host receptors and direct-acting antivirals targeting DENV structural and non-structural proteins are reviewed. In addition, the development of antivirals that target different stages during post-infection such as viral replication, viral maturation, and viral assembly are reviewed. Antiviral agents designed based on these molecular mechanisms of action could lead to the discovery and development of novel anti-DENV therapeutics for the treatment of dengue infections. Evaluations of combinations of antiviral drugs with different mechanisms of action could also lead to the development of synergistic drug combinations for the treatment of dengue at any stage of the infection. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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12 pages, 1284 KiB

Open AccessReview

Direct-Acting Antiviral Agents for Hepatitis C Virus Infection—From Drug Discovery to Successful Implementation in Clinical Practice

by Christopher Dietz and Benjamin Maasoumy

Viruses 2022, 14(6), 1325; https://doi.org/10.3390/v14061325 - 17 Jun 2022

Cited by 20 | Viewed by 3832

Abstract

Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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20 pages, 1631 KiB

Open AccessReview

Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity

by Ikbel Hadj Hassine, Manel Ben M’hadheb and Luis Menéndez-Arias

Viruses 2022, 14(4), 841; https://doi.org/10.3390/v14040841 - 18 Apr 2022

Cited by 30 | Viewed by 4735

Abstract

In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV infectivity has been observed after passage in 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2′-deoxycytidine while producing a two-fold increase in the viral mutation frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a prodrug of β-d-N⁴-hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and genotoxicity are important concerns limiting their extended use in antiviral therapy. Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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7 pages, 2155 KiB

Open AccessReview

FV-100 for the Treatment of Varicella-Virus (VZV) Infections: Quo Vadis?

by Erik De Clercq

Viruses 2022, 14(4), 770; https://doi.org/10.3390/v14040770 - 7 Apr 2022

Cited by 11 | Viewed by 2410

Abstract

The bicyclic nucleoside analogue (BCNA) Cf1743 and its orally bioavailable prodrug FV-100 have unique potential as varicella-zoster virus (VZV) inhibitors to treat herpes zoster (shingles) and the therewith associated pain, including post-herpetic neuralgia (PHN). The anti-VZV activity of Cf1743 depends on a specific phosphorylation by the VZV-encoded thymidine kinase (TK). The target of antiviral action is assumed to be the viral DNA polymerase (or DNA synthesis in the virus-infected cells). Full article

(This article belongs to the Special Issue Antiviral Molecular Mechanisms)

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