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Strategies in the Design and Development of Antiviral Drugs
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Strategies in the Design and Development of Antiviral Drugs

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (1 February 2025) | Viewed by 15325

Special Issue Editors

Dr. Shiv Bharadwaj

E-Mail Website
Guest Editor
Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, v.v.i., BIOCEV Research Center, Vestec, Czech Republic
Interests: drug discovery; viral informatics; viral infections; therapeutic molecules; protein chemistry; computational modeling
Prof. Dr. Umesh Yadava

E-Mail Website
Guest Editor
Department of Physics, Deen Dayal Upadhyaya Gorakhpur University, Gorakhpur, India
Interests: crystallography; computational chemistry; drug designing and synthesis; molecular dynamics; microbiology; virology
Dr. Amaresh Kumar Sahoo

E-Mail Website
Guest Editor
Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad 211015, Uttar Pradesh, India
Interests: drug discovery; nanobiotechnology; drug delivery systems; computational modeling; biosensors

Special Issue Information

Dear Colleagues,

Viruses are among the most infectious pathogens, responsible for the highest number of deaths worldwide. Each year, mortality linked with viral infections, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), dengue virus, Japanese encephalitis virus, and Zika virus, has been remarkable, while new pathogenic viral strains or variants are emerging because of high genetic recombination or cross-species transmission, as is the case with the ongoing COVID-19 pandemic. Consequently, there is an urgent need for the development of novel antiviral therapeutics that will allow health professionals to cure these viruses after infection or to combat the emerging viral infections.

Recently, advanced therapeutic synthetic drug molecules, bioactive, aptamers, peptides, and drug-conjugates have found extensive applications in the fields of drug discovery using both computational and experimental approaches. The perspective of using such therapeutic agents is to find the non-toxic, selective, and specific antiviral for a single genus or target more than one genotype of the target viruses simultaneously showing promising results to be considered for further clinical trials or applications.

In the present Special Issue entitled “Strategies in the Design and Development of Antiviral Drugs”, we are inviting original research, as well as review articles, which are related to the identification, synthesis, and evaluation of direct-acting antiviral or host-targeting agents that inhibit viral replication or pathogenesis. Furthermore, we also welcome the submission of mechanistic studies of new small organic molecules, metal complexes, and natural products, as well as studies on drug resistance, the in silico design of antiviral agents, and antiviral target validation.

Dr. Shiv Bharadwaj
Prof. Dr. Umesh Yadava
Dr. Amaresh Kumar Sahoo
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. Molecules is an international peer-reviewed open access semimonthly 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

  • antiviral drug
  • drug design
  • computational modeling
  • viral informatics
  • therapeutics
  • medicinal chemistry
  • innovative drug research
  • antiviral mechanisms
  • drug resistance
  • natural resources
  • synthetic drugs

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Published Papers (6 papers)

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Research

Jump to: Review

16 pages, 2891 KiB  
Article
Oxymatrine Modulation of TLR3 Signaling: A Dual-Action Mechanism for H9N2 Avian Influenza Virus Defense and Immune Regulation
by Yan Zhi, Xinping Zhao, Zhenyi Liu, Guoyu Shen, Taiming Zhang, Tao Zhang and Ge Hu
Molecules 2024, 29(9), 1945; https://doi.org/10.3390/molecules29091945 - 24 Apr 2024
Cited by 1 | Viewed by 1879
Abstract
In our research, we explored a natural substance called Oxymatrine, found in a traditional Chinese medicinal plant, to fight against a common bird flu virus known as H9N2. This virus not only affects birds but can also pose a threat to human health. [...] Read more.
In our research, we explored a natural substance called Oxymatrine, found in a traditional Chinese medicinal plant, to fight against a common bird flu virus known as H9N2. This virus not only affects birds but can also pose a threat to human health. We focused on how this natural compound can help in stopping the virus from spreading in cells that line the lungs of birds and potentially humans. Our findings show that Oxymatrine can both directly block the virus and boost the body’s immune response against it. This dual-action mechanism is particularly interesting because it indicates that Oxymatrine might be a useful tool in developing new ways to prevent and treat this type of bird flu. Understanding how Oxymatrine works against the H9N2 virus could lead to safer and more natural ways to combat viral infections in animals and humans, contributing to the health and well-being of society. The H9N2 Avian Influenza Virus (AIV) is a persistent health threat because of its rapid mutation rate and the limited efficacy of vaccines, underscoring the urgent need for innovative therapies. This study investigated the H9N2 AIV antiviral properties of Oxymatrine (OMT), a compound derived from traditional Chinese medicine, particularly focusing on its interaction with pulmonary microvascular endothelial cells (PMVECs). Employing an array of in vitro assays, including 50% tissue culture infectious dose, Cell Counting Kit-8, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot, we systematically elucidated the multifaceted effects of OMT. OMT dose-dependently inhibited critical antiviral proteins (PKR and Mx1) and modulated the expression of type I interferons and key cytokines (IFN-α, IFN-β, IL-6, and TNF-α), thereby affecting TLR3 signaling and its downstream elements (NF-κB and IRF-3). OMT’s antiviral efficacy extended beyond TLR3-mediated responses, suggesting its potential as a versatile antiviral agent. This study not only contributes to the growing body of research on the use of natural compounds as antiviral agents but also underscores the importance of further investigating the broader application of OMT for combating viral infections. Full article
(This article belongs to the Special Issue Strategies in the Design and Development of Antiviral Drugs)
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15 pages, 14174 KiB  
Article
Dapoxetine, a Selective Serotonin Reuptake Inhibitor, Suppresses Zika Virus Infection In Vitro
by Bingzhi Zhang, Jianchen Yu, Ge Zhu, Yun Huang, Kexin Zhang, Xuhan Xiao, Wenxuan He, Jie Yuan and Xiaoxia Gao
Molecules 2023, 28(24), 8142; https://doi.org/10.3390/molecules28248142 - 17 Dec 2023
Cited by 1 | Viewed by 2856
Abstract
Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family, and is a pathogen posing a significant threat to human health. Currently, there is a lack of internationally approved antiviral drugs for the treatment of ZIKV infection, and symptomatic management remains [...] Read more.
Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family, and is a pathogen posing a significant threat to human health. Currently, there is a lack of internationally approved antiviral drugs for the treatment of ZIKV infection, and symptomatic management remains the primary clinical approach. Consequently, the exploration of safe and effective anti-ZIKV drugs has emerged as a paramount imperative in ZIKV control efforts. In this study, we performed a screening of a compound library consisting of 1789 FDA-approved drugs to identify potential agents with anti-ZIKV activity. We have identified dapoxetine, an orally administered selective serotonin reuptake inhibitor (SSRI) commonly employed for the clinical management of premature ejaculation (PE), as a potential inhibitor of ZIKV RNA-dependent RNA polymerase (RdRp). Consequently, we conducted surface plasmon resonance (SPR) analysis to validate the specific binding of dapoxetine to ZIKV RdRp, and further evaluated its inhibitory effect on ZIKV RdRp synthesis using the ZIKV Gluc reporter gene assay. Furthermore, we substantiated the efficacy of dapoxetine in suppressing intracellular replication of ZIKV, thereby demonstrating a concentration-dependent antiviral effect (EC50 values ranging from 4.20 μM to 12.6 μM) and negligible cytotoxicity (CC50 > 50 μM) across diverse cell lines. Moreover, cell fluorescence staining and Western blotting assays revealed that dapoxetine effectively reduced the expression of ZIKV proteins. Collectively, our findings suggest that dapoxetine exhibits anti-ZIKV effects by inhibiting ZIKV RdRp activity, positioning it as a potential candidate for clinical therapeutic intervention against ZIKV infection. Full article
(This article belongs to the Special Issue Strategies in the Design and Development of Antiviral Drugs)
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13 pages, 1440 KiB  
Article
Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
by Sergi Chumillas, Saurabh Loharch, Manuela Beltrán, Mateusz P. Szewczyk, Silvia Bernal, Maria C. Puertas, Javier Martinez-Picado, José Alcamí, Luis M. Bedoya, Vicente Marchán and José Gallego
Molecules 2023, 28(20), 7031; https://doi.org/10.3390/molecules28207031 - 11 Oct 2023
Cited by 1 | Viewed by 2534
Abstract
Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, [...] Read more.
Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE–Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE–Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE–Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function. Full article
(This article belongs to the Special Issue Strategies in the Design and Development of Antiviral Drugs)
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22 pages, 12258 KiB  
Article
Pharmacoinformatics and Breed-Based De Novo Hybridization Studies to Develop New Neuraminidase Inhibitors as Potential Anti-Influenza Agents
by Bourougaa Lotfi, Ouassaf Mebarka, Bader Y. Alhatlani, Emad M. Abdallah and Sarkar M. A. Kawsar
Molecules 2023, 28(18), 6678; https://doi.org/10.3390/molecules28186678 - 18 Sep 2023
Cited by 8 | Viewed by 2064
Abstract
Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected [...] Read more.
Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected cell to host cells. As such, neuraminidase has emerged as a pivotal target for mitigating influenza and its associated complications. Here, we apply a de novo hybridization approach based on a breed-centric methodology to elucidate novel neuraminidase inhibitors. The breed technique amalgamates established ligand frameworks with the shared target, neuraminidase, resulting in innovative inhibitor constructs. Molecular docking analysis revealed that the seven synthesized breed molecules (designated Breeds 1–7) formed more robust complexes with the neuraminidase receptor than conventional clinical neuraminidase inhibitors such as zanamivir, oseltamivir, and peramivir. Pharmacokinetic evaluations of the seven breed molecules (Breeds 1–7) demonstrated favorable bioavailability and optimal permeability, all falling within the specified parameters for human application. Molecular dynamics simulations spanning 100 nanoseconds corroborated the stability of these breed molecules within the active site of neuraminidase, shedding light on their structural dynamics. Binding energy assessments, which were conducted through MM-PBSA analysis, substantiated the enduring complexes formed by the seven types of molecules and the neuraminidase receptor. Last, the investigation employed a reaction-based enumeration technique to ascertain the synthetic pathways for the synthesis of the seven breed molecules. Full article
(This article belongs to the Special Issue Strategies in the Design and Development of Antiviral Drugs)
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Review

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24 pages, 2743 KiB  
Review
Insights into SARS-CoV-2: Small-Molecule Hybrids for COVID-19 Treatment
by Maria Luisa Navacchia, Caterina Cinti, Elena Marchesi and Daniela Perrone
Molecules 2024, 29(22), 5403; https://doi.org/10.3390/molecules29225403 - 15 Nov 2024
Cited by 1 | Viewed by 1688
Abstract
The advantages of a treatment modality that combines two or more therapeutic agents with different mechanisms of action encourage the study of hybrid functional compounds for pharmacological applications. Molecular hybridization, resulting from a covalent combination of two or more pharmacophore units, has emerged [...] Read more.
The advantages of a treatment modality that combines two or more therapeutic agents with different mechanisms of action encourage the study of hybrid functional compounds for pharmacological applications. Molecular hybridization, resulting from a covalent combination of two or more pharmacophore units, has emerged as a promising approach to overcome several issues and has also been explored for the design of new drugs for COVID-19 treatment. In this review, we presented an overview of small-molecule hybrids from both natural products and synthetic sources reported in the literature to date with potential antiviral anti-SARS-CoV-2 activity. Full article
(This article belongs to the Special Issue Strategies in the Design and Development of Antiviral Drugs)
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31 pages, 4638 KiB  
Review
The Role of Peptides in Combatting HIV Infection: Applications and Insights
by Naiera M. Helmy and Keykavous Parang
Molecules 2024, 29(20), 4951; https://doi.org/10.3390/molecules29204951 - 19 Oct 2024
Cited by 1 | Viewed by 2893
Abstract
Peptide-based inhibitors represent a promising approach for the treatment of HIV-1, offering a range of potential advantages, including specificity, low toxicity, and the ability to target various stages of the viral lifecycle. This review outlines the current state of research on peptide-based anti-HIV [...] Read more.
Peptide-based inhibitors represent a promising approach for the treatment of HIV-1, offering a range of potential advantages, including specificity, low toxicity, and the ability to target various stages of the viral lifecycle. This review outlines the current state of research on peptide-based anti-HIV therapies, highlighting key advancements and identifying future research directions. Over the past few years, there has been significant progress in developing synthetic peptide-based drugs that target various stages of the viral life cycle, including entry and replication. These approaches aim to create effective anti-HIV therapies. Additionally, peptides have proven valuable in the development of anti-HIV vaccines. In the quest for effective HIV vaccines, discovering potent antigens and designing suitable vaccine strategies are crucial for overcoming challenges such as low immunogenicity, safety concerns, and increased viral load. Innovative strategies for vaccine development through peptide research are, therefore, a key focus area for achieving effective HIV prevention. This review aims to explore the strategies for designing peptides with anti-HIV activity and to highlight their role in advancing both therapeutic and preventive measures against HIV. Full article
(This article belongs to the Special Issue Strategies in the Design and Development of Antiviral Drugs)
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