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Antiviral Drug Targets: Structure, Function, and Drug Design
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Antiviral Drug Targets: Structure, Function, and Drug Design

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 29551

Special Issue Editors

Dr. Mattia Mori

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: zinc-binding proteins; medicinal chemistry; molecular dynamics; virtual screening; natural products; antiviral agents; anticancer agents; chemoinformatics; computational structural biology; lead optimization
Special Issues, Collections and Topics in MDPI journals
Dr. Ilaria Vicenti

E-Mail Website
Guest Editor
Department of Medical Biotechnologies, University of Siena, Siena, Italy
Interests: flaviviruses; antivirals; cell-based viral assays; drug resistance; HIV-1, SARS-COV-2
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Today, viral infections represent a serious health and social problem, as underlined by the current coronavirus pandemic. Several other viruses (e.g., Ebola, Zika, West Nile, Dengue, and Chikungunya virus) for which drugs or vaccines might not be available represent a concrete risk of epidemics. Antiviral drug design requires contributions from different disciplines: characterization of the virus type, elucidation of structural features of macromolecular targets, and understanding of the mechanisms of viral replication into the host notably accelerate the identification of suitable drug targets. Antiviral agents are designed and optimized accordingly, through multiple techniques including computational, chemical, biochemical, biophysical, and biological studies, as well as integrated combinations of them.

This Special Issue collects recent findings on antiviral drug targets with a focus on structural and functional elucidations, and drug design. The submission of original research papers and reviews on this broad and relevant topic is warmly welcome.

Dr. Mattia Mori
Dr. Ilaria Vicenti
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 infections
  • drug design
  • protein structures
  • functional studies
  • viruses
  • antiviral drugs

Related Special Issue

Published Papers (7 papers)

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Research

Jump to: Review

22 pages, 4546 KiB  
Article
Rapid Reversible Osmoregulation of Cytoplasmic Biomolecular Condensates of Human Interferon-α-Induced Antiviral MxA GTPase
by Pravin B. Sehgal, Huijuan Yuan and Ye Jin
Int. J. Mol. Sci. 2022, 23(21), 12739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112739 - 22 Oct 2022
Cited by 1 | Viewed by 1400
Abstract
We previously discovered that exogenously expressed GFP-tagged cytoplasmic human myxovirus resistance protein (MxA), a major antiviral effector of Type I and III interferons (IFNs) against several RNA- and DNA-containing viruses, existed in the cytoplasm in phase-separated membraneless biomolecular condensates of varying sizes and [...] Read more.
We previously discovered that exogenously expressed GFP-tagged cytoplasmic human myxovirus resistance protein (MxA), a major antiviral effector of Type I and III interferons (IFNs) against several RNA- and DNA-containing viruses, existed in the cytoplasm in phase-separated membraneless biomolecular condensates of varying sizes and shapes with osmotically regulated disassembly and reassembly. In this study we investigated whether cytoplasmic IFN-α-induced endogenous human MxA structures were also biomolecular condensates, displayed hypotonic osmoregulation and the mechanisms involved. Both IFN-α-induced endogenous MxA and exogenously expressed GFP-MxA formed cytoplasmic condensates in A549 lung and Huh7 hepatoma cells which rapidly disassembled within 1–2 min when cells were exposed to 1,6-hexanediol or to hypotonic buffer (~40–50 mOsm). Both reassembled into new structures within 1–2 min of shifting cells to isotonic culture medium (~330 mOsm). Strikingly, MxA condensates in cells continuously exposed to culture medium of moderate hypotonicity (in the range one-fourth, one-third or one-half isotonicity; range 90–175 mOsm) first rapidly disassembled within 1–3 min, and then, in most cells, spontaneously reassembled 7–15 min later into new structures. This spontaneous reassembly was inhibited by 2-deoxyglucose (thus, was ATP-dependent) and by dynasore (thus, required membrane internalization). Indeed, condensate reassembly was preceded by crowding of the cytosolic space by large vacuole-like dilations (VLDs) derived from internalized plasma membrane. Remarkably, the antiviral activity of GFP-MxA against vesicular stomatitis virus survived hypoosmolar disassembly and subsequent reassembly. The data highlight the exquisite osmosensitivity of MxA condensates, and the preservation of antiviral activity in the face of hypotonic stress. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
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19 pages, 3532 KiB  
Article
Two Ligand-Binding Sites on SARS-CoV-2 Non-Structural Protein 1 Revealed by Fragment-Based X-ray Screening
by Shumeng Ma, Shymaa Damfo, Jiaqi Lou, Nikos Pinotsis, Matthew W. Bowler, Shozeb Haider and Frank Kozielski
Int. J. Mol. Sci. 2022, 23(20), 12448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012448 - 18 Oct 2022
Cited by 8 | Viewed by 3132
Abstract
The regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. The most recent and still ongoing novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has brought a range [...] Read more.
The regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. The most recent and still ongoing novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has brought a range of devastating consequences. Due to the exceptionally fast development of vaccines, the mortality rate of the virus has been curbed to a significant extent. However, the limitations of vaccination efficiency and applicability, coupled with the still high infection rate, emphasise the urgent need for discovering safe and effective antivirals against SARS-CoV-2 by suppressing its replication or attenuating its virulence. Non-structural protein 1 (nsp1), a unique viral and conserved leader protein, is a crucial virulence factor for causing host mRNA degradation, suppressing interferon (IFN) expression and host antiviral signalling pathways. In view of the essential role of nsp1 in the CoV life cycle, it is regarded as an exploitable target for antiviral drug discovery. Here, we report a variety of fragment hits against the N-terminal domain of SARS-CoV-2 nsp1 identified by fragment-based screening via X-ray crystallography. We also determined the structure of nsp1 at atomic resolution (0.99 Å). Binding affinities of hits against nsp1 and potential stabilisation were determined by orthogonal biophysical assays such as microscale thermophoresis and thermal shift assays. We identified two ligand-binding sites on nsp1, one deep and one shallow pocket, which are not conserved between the three medically relevant SARS, SARS-CoV-2 and MERS coronaviruses. Our study provides an excellent starting point for the development of more potent nsp1-targeting inhibitors and functional studies on SARS-CoV-2 nsp1. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
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12 pages, 2207 KiB  
Article
In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction
by Alice Sosic, Giulia Olivato, Caterina Carraro, Richard Göttlich, Dan Fabris and Barbara Gatto
Int. J. Mol. Sci. 2022, 23(2), 582; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020582 - 06 Jan 2022
Cited by 2 | Viewed by 1256
Abstract
After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with [...] Read more.
After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
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28 pages, 14278 KiB  
Article
Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors
by Robert Reiberger, Kateřina Radilová, Michal Kráľ, Václav Zima, Pavel Majer, Jiří Brynda, Martin Dračínský, Jan Konvalinka, Milan Kožíšek and Aleš Machara
Int. J. Mol. Sci. 2021, 22(14), 7735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147735 - 20 Jul 2021
Cited by 9 | Viewed by 4775
Abstract
The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme’s [...] Read more.
The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme’s catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3′,4′-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
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16 pages, 1587 KiB  
Article
Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro
by Adele Boccuto, Filippo Dragoni, Francesca Picarazzi, Alessia Lai, Carla Della Ventura, Carla Veo, Federica Giammarino, Francesco Saladini, Gianguglielmo Zehender, Maurizio Zazzi, Mattia Mori and Ilaria Vicenti
Int. J. Mol. Sci. 2021, 22(5), 2670; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052670 - 06 Mar 2021
Cited by 4 | Viewed by 2115
Abstract
The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection [...] Read more.
The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC50) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC50 shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
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Review

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20 pages, 2747 KiB  
Review
Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects
by Julia M. Smyk, Natalia Szydłowska, Weronika Szulc and Anna Majewska
Int. J. Mol. Sci. 2022, 23(20), 12244; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012244 - 13 Oct 2022
Cited by 19 | Viewed by 3404
Abstract
Viral evolution refers to the genetic changes that a virus accumulates during its lifetime which can arise from adaptations in response to environmental changes or the immune response of the host. Influenza A virus is one of the most rapidly evolving microorganisms. Its [...] Read more.
Viral evolution refers to the genetic changes that a virus accumulates during its lifetime which can arise from adaptations in response to environmental changes or the immune response of the host. Influenza A virus is one of the most rapidly evolving microorganisms. Its genetic instability may lead to large changes in its biological properties, including changes in virulence, adaptation to new hosts, and even the emergence of infectious diseases with a previously unknown clinical course. Genetic variability makes it difficult to implement effective prophylactic programs, such as vaccinations, and may be responsible for resistance to antiviral drugs. The aim of the review was to describe the consequences of the variability of influenza viruses, mutations, and recombination, which allow viruses to overcome species barriers, causing epidemics and pandemics. Another consequence of influenza virus evolution is the risk of the resistance to antiviral drugs. Thus far, one class of drugs, M2 protein inhibitors, has been excluded from use because of mutations in strains isolated in many regions of the world from humans and animals. Therefore, the effectiveness of anti-influenza drugs should be continuously monitored in reference centers representing particular regions of the world as a part of epidemiological surveillance. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
33 pages, 3851 KiB  
Review
40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?
by Anna Majewska and Beata Mlynarczyk-Bonikowska
Int. J. Mol. Sci. 2022, 23(7), 3431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073431 - 22 Mar 2022
Cited by 31 | Viewed by 11386
Abstract
Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild [...] Read more.
Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild and self-limiting, but in immunocompromised patients, such as solid organ or bone marrow transplant recipients, the course can be very severe or even life-threatening. Unfortunately, in the latter group, the highest percentage of infections with strains resistant to routinely used drugs is observed. On the other hand, frequent recurrences of genital herpes can be a problem even in people with normal immunity. Genital herpes also increases the risk of acquiring sexually transmitted diseases, including HIV infection and, if present in pregnant women, poses a risk to the fetus and newborn. Even more frequently than herpes simplex, congenital infections can be caused by cytomegalovirus. We present the most important anti-herpesviral agents, the mechanisms of resistance to these drugs, and the associated mutations in the viral genome. Special emphasis was placed on newly introduced drugs such as maribavir and brincidofovir. We also briefly discuss the most promising substances in preclinical testing as well as immunotherapy options and vaccines currently in use and under investigation. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design)
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