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Biomolecules
Special Issues
Viral Drug Targets and Discovery of Antiviral Agents
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Viral Drug Targets and Discovery of Antiviral Agents

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (5 March 2024) | Viewed by 6474

Special Issue Editors

Dr. Haitao Yang

E-Mail Website
Guest Editor
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Interests: virus; drug target; structure-based drug design; drug screen; virus–host interactions
Dr. Wei Wang

E-Mail Website
Guest Editor
Institute of Life Sciences, Chongqing Medical University, Chongqing, China
Interests: virus; virus-host interactions; viral RNA

Special Issue Information

Dear Colleagues,

In the last twenty years, there have been many regional or global outbreaks of viral diseases, which have caused significant economic costs and posed serious threats to global health. The ongoing COVID-19 pandemic has caused prominent global health challenges. Although vaccines and targeted therapies are under development to control these infections, potent drugs are very limited. The antivirals may target essential stages of the viral life cycle, including cellular entry, the replication and transcription of the viral genome, virion assembly and release, and virus–host interactions.  

Since the first antiviral drug, acyclovir, was approved to treat herpes simplex virus infections in the 1980s, attempts to develop drugs against a number of viral infections have been ongoing for decades. However, antiviral development faces many challenges. (1) The development of antivirals usually lags behind the development of antibiotics against bacterial infections because viral genomes are generally smaller than bacterial ones, which suggests that viruses have fewer targets for drug development. (2) The lack of cell and animal models can present obstacles for testing drug efficacy. (3) The antiviral drugs targeting the viral cycle or host cellular factors need to avoid causing severe side-effects. (4) The emergence of viral mutants causes drug resistance.

In this Special Issue of Biomolecules, we intend to discuss multiple aspects of key targets in relation to virus cycles, antivirals directly against viral proteins, and host-targeting inhibitors to gain a deep understanding of the molecular mechanisms of action for the compounds, which may accelerate the antiviral drug development process. The scientific community may contribute original research, reviews, and opinions. The approaches and techniques addressed in the manuscripts will encompass multiple disciplines: virology, molecular biology, biochemistry, biophysics, structural biology, cell biology, immunology, computational biology, and pharmacology. All are welcome.

Dr. Haitao Yang
Dr. Wei Wang
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. Biomolecules 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 2700 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

  • drug target
  • drug design
  • structural biology
  • high-throughput screening
  • antiviral
  • virus

Published Papers (4 papers)

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13 pages, 1488 KiB  
Article
Unwinding the SARS-CoV-2 Ribosomal Frameshifting Pseudoknot with LNA and G-Clamp-Modified Phosphorothioate Oligonucleotides Inhibits Viral Replication
by Ekaterina Knizhnik, Stepan Chumakov, Julia Svetlova, Iulia Pavlova, Yuri Khodarovich, Vladimir Brylev, Vjacheslav Severov, Rugiya Alieva, Liubov Kozlovskaya, Dmitry Andreev, Andrey Aralov and Anna Varizhuk
Biomolecules 2023, 13(11), 1660; https://doi.org/10.3390/biom13111660 - 17 Nov 2023
Viewed by 1486
Abstract
Ribosomal frameshifting (RFS) at the slippery site of SARS-CoV-2 RNA is essential for the biosynthesis of the viral replication machinery. It requires the formation of a pseudoknot (PK) structure near the slippery site and can be inhibited by PK-disrupting oligonucleotide-based antivirals. We obtained [...] Read more.
Ribosomal frameshifting (RFS) at the slippery site of SARS-CoV-2 RNA is essential for the biosynthesis of the viral replication machinery. It requires the formation of a pseudoknot (PK) structure near the slippery site and can be inhibited by PK-disrupting oligonucleotide-based antivirals. We obtained and compared three types of such antiviral candidates, namely locked nucleic acids (LNA), LNA–DNA gapmers, and G-clamp-containing phosphorothioates (CPSs) complementary to PK stems. Using optical and electrophoretic methods, we showed that stem 2-targeting oligonucleotide analogs induced PK unfolding at nanomolar concentrations, and this effect was particularly pronounced in the case of LNA. For the leading PK-unfolding LNA and CPS oligonucleotide analogs, we also demonstrated dose-dependent RSF inhibition in dual luciferase assays (DLAs). Finally, we showed that the leading oligonucleotide analogs reduced SARS-CoV-2 replication at subtoxic concentrations in the nanomolar range in two human cell lines. Our findings highlight the promise of PK targeting, illustrate the advantages and limitations of various types of DNA modifications and may promote the future development of oligonucleotide-based antivirals. Full article
(This article belongs to the Special Issue Viral Drug Targets and Discovery of Antiviral Agents)
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12 pages, 294 KiB  
Article
Efficacy and Safety of Anti-SARS-CoV-2 Antiviral Agents and Monoclonal Antibodies in Patients with SLE: A Case-Control Study
by Giuseppe A. Ramirez, Maria Gerosa, Chiara Bellocchi, Daniel Arroyo-Sánchez, Chiara Asperti, Lorenza M. Argolini, Gabriele Gallina, Martina Cornalba, Isabella Scotti, Ilaria Suardi, Luca Moroni, Lorenzo Beretta, Enrica P. Bozzolo, Roberto Caporali and Lorenzo Dagna
Biomolecules 2023, 13(9), 1273; https://doi.org/10.3390/biom13091273 - 22 Aug 2023
Cited by 2 | Viewed by 1333
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19) has spread pandemically with high rates of morbidity and mortality. COVID-19 has also posed unprecedented challenges in terms of rapid development of pharmacological countermeasures to prevent or contrast SARS-CoV-2 pathogenicity. Anti-SARS-CoV-2 antiviral agents and [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19) has spread pandemically with high rates of morbidity and mortality. COVID-19 has also posed unprecedented challenges in terms of rapid development of pharmacological countermeasures to prevent or contrast SARS-CoV-2 pathogenicity. Anti-SARS-CoV-2 antiviral agents and monoclonal antibodies have been specifically designed to attenuate COVID-19 morbidity and prevent mortality in vulnerable subjects, such as patients with immune-mediated diseases, but evidence for the safe and effective use of these drugs in this latter population group is scarce. Therefore, we designed a retrospective, multicentre, observational, case-control study to analyse the impact of these treatments in COVID-19 patients with systemic lupus erythematosus (SLE), a paradigmatic, multi-organ autoimmune disease. We identified 21 subjects treated with antivirals and/or monoclonal antibodies who were matched with 42 untreated patients by age, sex, SLE extension and duration. Treated patients had higher baseline SLE disease activity index 2000 scores [SLEDAI-2K median (interquartile range) = 4 (1–5) vs. 0 (0–2); p = 0.009], higher prednisone doses [5 (0–10) mg vs. 0 (0–3) mg; p = 0.002], and more severe COVID-19 symptoms by a five-point World Health Organisation-endorsed analogue scale [1 (0–1) vs. 0 (0–1); p < 0.010] compared to untreated patients. There was no difference between groups in terms of COVID-19 outcomes and sequelae, nor in terms of post-COVID-19 SLE exacerbations. Three subjects reported mild adverse events (two with monoclonal antibodies, one with nirmatrelvir/ritonavir). These data suggest that anti-SARS-CoV-2 antivirals and monoclonal antibodies might be safely and effectively used in patients with SLE, especially with active disease and more severe COVID-19 symptoms at presentation. Full article
(This article belongs to the Special Issue Viral Drug Targets and Discovery of Antiviral Agents)
22 pages, 3658 KiB  
Article
The Metallodrug BOLD-100 Is a Potent Inhibitor of SARS-CoV-2 Replication and Has Broad-Acting Antiviral Activity
by Daniel S. Labach, Hinissan P. Kohio, Edwin A. Tse, Ermela Paparisto, Nicole J. Friesen, Jim Pankovich, Mark Bazett and Stephen D. Barr
Biomolecules 2023, 13(7), 1095; https://doi.org/10.3390/biom13071095 - 8 Jul 2023
Cited by 2 | Viewed by 1671
Abstract
The COVID-19 pandemic has highlighted an urgent need to discover and test new drugs to treat patients. Metal-based drugs are known to interact with DNA and/or a variety of proteins such as enzymes and transcription factors, some of which have been shown to [...] Read more.
The COVID-19 pandemic has highlighted an urgent need to discover and test new drugs to treat patients. Metal-based drugs are known to interact with DNA and/or a variety of proteins such as enzymes and transcription factors, some of which have been shown to exhibit anticancer and antimicrobial effects. BOLD-100 (sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]dihydrate) is a novel ruthenium-based drug currently being evaluated in a Phase 1b/2a clinical trial for the treatment of advanced gastrointestinal cancer. Given that metal-based drugs are known to exhibit antimicrobial activities, we asked if BOLD-100 exhibits antiviral activity towards SARS-CoV-2. We demonstrated that BOLD-100 potently inhibits SARS-CoV-2 replication and cytopathic effects in vitro. An RNA sequencing analysis showed that BOLD-100 inhibits virus-induced transcriptional changes in infected cells. In addition, we showed that the antiviral activity of BOLD-100 is not specific for SARS-CoV-2, but also inhibits the replication of the evolutionarily divergent viruses Human Immunodeficiency Virus type 1 and Human Adenovirus type 5. This study identifies BOLD-100 as a potentially novel broad-acting antiviral drug. Full article
(This article belongs to the Special Issue Viral Drug Targets and Discovery of Antiviral Agents)
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11 pages, 3766 KiB  
Brief Report
Treatment-Emergent Cilgavimab Resistance Was Uncommon in Vaccinated Omicron BA.4/5 Outpatients
by Cesare Ernesto Maria Gruber, Fabio Giovanni Tucci, Martina Rueca, Valentina Mazzotta, Giulia Gramigna, Alessandra Vergori, Lavinia Fabeni, Giulia Berno, Emanuela Giombini, Ornella Butera, Daniele Focosi, Ingrid Guarnetti Prandi, Giovanni Chillemi, Emanuele Nicastri, Francesco Vaia, Enrico Girardi, Andrea Antinori and Fabrizio Maggi
Biomolecules 2023, 13(10), 1538; https://doi.org/10.3390/biom13101538 - 18 Oct 2023
Cited by 1 | Viewed by 1333
Abstract
Mutations in the SARS-CoV-2 Spike glycoprotein can affect monoclonal antibody efficacy. Recent findings report the occurrence of resistant mutations in immunocompromised patients after tixagevimab/cilgavimab treatment. More recently, the Food and Drug Agency revoked the authorization for tixagevimab/cilgavimab, while this monoclonal antibody cocktail is [...] Read more.
Mutations in the SARS-CoV-2 Spike glycoprotein can affect monoclonal antibody efficacy. Recent findings report the occurrence of resistant mutations in immunocompromised patients after tixagevimab/cilgavimab treatment. More recently, the Food and Drug Agency revoked the authorization for tixagevimab/cilgavimab, while this monoclonal antibody cocktail is currently recommended by the European Medical Agency. We retrospectively reviewed 22 immunocompetent patients at high risk for disease progression who received intramuscular tixagevimab/cilgavimab as early COVID-19 treatment and presented a prolonged high viral load. Complete SARS-CoV-2 genome sequences were obtained for a deep investigation of mutation frequencies in Spike protein before and during treatment. At seven days, only one patient showed evidence of treatment-emergent cilgavimab resistance. Quasispecies analysis revealed two different deletions on the Spike protein (S:del138–144 or S:del141–145) in combination with the resistance S:K444N mutation. The structural and dynamic impact of the two quasispecies was characterized by using molecular dynamics simulations, showing the conservation of the principal functional movements in the mutated systems and their capabilities to alter the structure and dynamics of the RBD, responsible for the interaction with the ACE2 human receptor. Our study underlines the importance of prompting an early virological investigation to prevent drug resistance or clinical failures in immunocompetent patients. Full article
(This article belongs to the Special Issue Viral Drug Targets and Discovery of Antiviral Agents)
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