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Antiviral Drug Targets: Structure, Function, and Drug Design 2.0

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

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 21420

Special Issue Editors


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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

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

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Keywords

  • viral infections
  • drug design
  • protein structures
  • functional studies
  • viruses
  • antiviral drugs

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Published Papers (8 papers)

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Research

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23 pages, 3112 KiB  
Article
Piperazine-Substituted Pyranopyridines Exhibit Antiproliferative Activity and Act as Inhibitors of HBV Virion Production
by Sona Buloyan, Arpine Harutyunyan, Hrachik Gasparyan, Anahit Sakeyan, Astghik Shahkhatuni, Natalia F. Zakirova, Gaukhar Yusubalieva, Ilya M. Kirillov, Irina T. Fedyakina, Pavel N. Solyev, Anastasia V. Lipatova, Mikhail A. Bogomolov, Vladimir S. Prassolov, Timofey D. Lebedev and Alexander V. Ivanov
Int. J. Mol. Sci. 2025, 26(9), 3991; https://doi.org/10.3390/ijms26093991 - 23 Apr 2025
Viewed by 767
Abstract
Advances in medicinal chemistry have led to the development of anticancer and anti-infectious drugs. However, many types of cancer and viral infections such as hepatitis B virus or SARS-CoV-2 are still treated ineffectively. Therefore, further development of effective and selective lead compounds as [...] Read more.
Advances in medicinal chemistry have led to the development of anticancer and anti-infectious drugs. However, many types of cancer and viral infections such as hepatitis B virus or SARS-CoV-2 are still treated ineffectively. Therefore, further development of effective and selective lead compounds as potential drugs is still highly demanded. In this study, we synthesized a novel series of piperazine-substituted pyranopyridines and evaluated their anticancer and antiviral properties. Antiproliferative activity was determined in a panel of various tumor cell lines as well as non-tumor hepatic HepaRG cells. Mechanisms of cytotoxicity were assessed by fluorescent microscopy techniques. Antiviral activity was analyzed towards DNA and RNA viruses in infectious cell culture systems. Several compounds showed antiproliferative activity towards various cancer cell lines at micromolar and submicromolar concentrations. Mechanisms of cytotoxicity involve the induction of apoptosis and are not mediated via ERK1/2 pathway or oxidative stress. Several compounds exhibit selective activity against hepatitis B virus by preventing the formation of virion particles. This study led to the identification of a novel class of piperazine-substituted pyranopyridines with antiproliferative activity towards a wide range of tumor cell lines as well as the non-toxic inhibitor of HBV virion production. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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16 pages, 2902 KiB  
Article
Exploring the Antiviral Potential of Natural Compounds against Influenza: A Combined Computational and Experimental Approach
by Vladimir Perovic, Kristina Stevanovic, Natalya Bukreyeva, Slobodan Paessler, Junki Maruyama, Sergi López-Serrano, Ayub Darji, Milan Sencanski, Draginja Radosevic, Simone Berardozzi, Bruno Botta, Mattia Mori and Sanja Glisic
Int. J. Mol. Sci. 2024, 25(9), 4911; https://doi.org/10.3390/ijms25094911 - 30 Apr 2024
Cited by 2 | Viewed by 1982
Abstract
The influenza A virus nonstructural protein 1 (NS1), which is crucial for viral replication and immune evasion, has been identified as a significant drug target with substantial potential to contribute to the fight against influenza. The emergence of drug-resistant influenza A virus strains [...] Read more.
The influenza A virus nonstructural protein 1 (NS1), which is crucial for viral replication and immune evasion, has been identified as a significant drug target with substantial potential to contribute to the fight against influenza. The emergence of drug-resistant influenza A virus strains highlights the urgent need for novel therapeutics. This study proposes a combined theoretical criterion for the virtual screening of molecular libraries to identify candidate NS1 inhibitors. By applying the criterion to the ZINC Natural Product database, followed by ligand-based virtual screening and molecular docking, we proposed the most promising candidate as a potential NS1 inhibitor. Subsequently, the selected natural compound was experimentally evaluated, revealing measurable virus replication inhibition activity in cell culture. This approach offers a promising avenue for developing novel anti-influenza agents targeting the NS1 protein. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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18 pages, 11466 KiB  
Article
A New Derivative of Retro-2 Displays Antiviral Activity against Respiratory Syncytial Virus
by Adrien Le Rouzic, Jenna Fix, Robin Vinck, Sandrine Kappler-Gratias, Romain Volmer, Franck Gallardo, Jean-François Eléouët, Mathilde Keck, Jean-Christophe Cintrat, Julien Barbier, Daniel Gillet and Marie Galloux
Int. J. Mol. Sci. 2024, 25(1), 415; https://doi.org/10.3390/ijms25010415 - 28 Dec 2023
Cited by 1 | Viewed by 1721
Abstract
Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in newborns, with all children being infected before the age of two. Reinfections are very common throughout life and can cause severe respiratory infections in the elderly and immunocompromised [...] Read more.
Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in newborns, with all children being infected before the age of two. Reinfections are very common throughout life and can cause severe respiratory infections in the elderly and immunocompromised adults. Although vaccines and preventive antibodies have recently been licensed for use in specific subpopulations of patients, there is still no therapeutic treatment commonly available for these infections. Here, we investigated the potential antiviral activity of Retro-2.2, a derivative of the cellular retrograde transport inhibitor Retro-2, against hRSV. We show that Retro-2.2 inhibits hRSV replication in cell culture and impairs the ability of hRSV to form syncytia. Our results suggest that Retro-2.2 treatment affects virus spread by disrupting the trafficking of the viral de novo synthetized F and G glycoproteins to the plasma membrane, leading to a defect in virion morphogenesis. Taken together, our data show that targeting intracellular transport may be an effective strategy against hRSV infection. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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16 pages, 1500 KiB  
Article
Synthesis and Antiviral and Antitumor Activities of Novel 18β-Glycyrrhetinic Acid Derivatives
by Bo-Wen Pan, Liang-Liang Zheng, Yang Shi, Zhang-Chao Dong, Ting-Ting Feng, Jian Yang, Ying Wei and Ying Zhou
Int. J. Mol. Sci. 2023, 24(19), 15012; https://doi.org/10.3390/ijms241915012 - 9 Oct 2023
Cited by 4 | Viewed by 1913
Abstract
A series of novel derivatives of 18β-glycyrrhetinic acid (GA) were synthesized by introducing aromatic or heterocyclic structures to extend the side chain, thereby enhancing their interaction with amino acid residues in the active pocket of the target protein. These compounds were [...] Read more.
A series of novel derivatives of 18β-glycyrrhetinic acid (GA) were synthesized by introducing aromatic or heterocyclic structures to extend the side chain, thereby enhancing their interaction with amino acid residues in the active pocket of the target protein. These compounds were structurally characterized using 1H NMR, 13C NMR, and HRMS. The compounds were subsequently evaluated for their inhibitory effects on HIV-1 protease and cell viability in the human cancer cell lines K562 and HeLa and the mouse cancer cell line CT26. Towards HIV-1 protease, compounds 28 and 32, which featured the introduction of heterocyclic moieties at the C3 position of GA, exhibited the highest inhibition, with inhibition rates of 76% and 70.5%, respectively, at 1 mg/mL concentration. Further molecular docking suggests that a 3-substituted polar moiety would be likely to enhance the inhibitory activity against HIV-1 protease. As for the anti-proliferative activities of the GA derivatives, incorporation of a thiazole heterocycle at the C3- position in compound 29 significantly enhanced the effect against K562 cells with an IC50 value of 8.86 ± 0.93 µM. The introduction of electron-withdrawing substituents on the C3-substituted phenyl ring augmented the anti-proliferative activity against Hela and CT26 cells. Compound 13 exhibited the highest inhibitory activity against Hela cells with an IC50 value of 9.89 ± 0.86 µM, whereas compound 7 exerted the strongest inhibition against CT26 cells with an IC50 value of 4.54 ± 0.37 µM. These findings suggest that further modification of GA is a promising path for developing potent novel anti-HIV and anticancer therapeutics. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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18 pages, 4821 KiB  
Article
The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection
by Hongya Ning, Shih-Hsin Chiu, Xiaodong Xu, Yanmei Ma, Ji-Long Chen and Guihong Yang
Int. J. Mol. Sci. 2023, 24(10), 8586; https://doi.org/10.3390/ijms24108586 - 11 May 2023
Cited by 7 | Viewed by 2674
Abstract
The clinical benefits of targeting programmed death-ligand 1 (PD-L1) in various cancers represent a strategy for the treatment of immunosuppressive diseases. Here, it was demonstrated that the expression levels of PD-L1 in cells were greatly upregulated in response to H1N1 influenza A virus [...] Read more.
The clinical benefits of targeting programmed death-ligand 1 (PD-L1) in various cancers represent a strategy for the treatment of immunosuppressive diseases. Here, it was demonstrated that the expression levels of PD-L1 in cells were greatly upregulated in response to H1N1 influenza A virus (IAV) infection. Overexpression of PD-L1 promoted viral replication and downregulated type-I and type-III interferons and interferon-stimulated genes. Moreover, the association between PD-L1 and Src homology region-2, containing protein tyrosine phosphatase (SHP2), during IAV/H1N1 infection was analyzed by employing the SHP2 inhibitor (SHP099), siSHP2, and pNL-SHP2. The results showed that the expressions of PD-L1 mRNA and protein were decreased under SHP099 or siSHP2 treatment, whereas the cells overexpressing SHP2 exhibited the opposite effects. Additionally, the effects of PD-L1 on the expression of p-ERK and p-SHP2 were investigated in PD-L1-overexpressed cells following WSN or PR8 infection, determining that the PD-L1 overexpression led to the decreased expression of p-SHP2 and p-ERK induced by WSN or PR8 infection. Taken together, these data reveal that PD-L1 could play an important role in immunosuppression during IAV/H1N1 infection; thus, it may serve as a promising therapeutic target for development of novel anti-IAV drugs. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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Review

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19 pages, 937 KiB  
Review
The Intrinsically Disordered Region of HBx and Virus–Host Interactions: Uncovering New Therapeutic Approaches for HBV and Cancer
by Rodrigo A. Villanueva and Alejandra Loyola
Int. J. Mol. Sci. 2025, 26(8), 3552; https://doi.org/10.3390/ijms26083552 - 10 Apr 2025
Viewed by 273
Abstract
Human viral infections remain a significant global health challenge, contributing to a substantial number of cancer cases worldwide. Among them, infections with oncoviruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) are key drivers of hepatocellular carcinoma (HCC). Despite the [...] Read more.
Human viral infections remain a significant global health challenge, contributing to a substantial number of cancer cases worldwide. Among them, infections with oncoviruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) are key drivers of hepatocellular carcinoma (HCC). Despite the availability of an effective HBV vaccine since the 1980s, millions remain chronically infected due to the persistence of covalently closed circular DNA (cccDNA) as a reservoir in hepatocytes. Current antiviral therapies, including nucleos(t)ide analogs and interferon, effectively suppress viral replication but fail to eliminate cccDNA, underscoring the urgent need for innovative therapeutic strategies. Direct-acting antiviral agents (DAAs), which have revolutionized HCV treatment with high cure rates, offer a promising model for HBV therapy. A particularly attractive target is the intrinsically disordered region (IDR) of the HBx protein, which regulates cccDNA transcription, viral replication, and oncogenesis by interacting with key host proteins. DAAs targeting these interactions could inhibit viral persistence, suppress oncogenic signaling, and overcome treatment resistance. This review highlights the potential of HBx-directed DAAs to complement existing therapies, offering renewed hope for a functional HBV cure and reduced cancer risk. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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33 pages, 1379 KiB  
Review
HPV Infections—Classification, Pathogenesis, and Potential New Therapies
by Beata Mlynarczyk-Bonikowska and Lidia Rudnicka
Int. J. Mol. Sci. 2024, 25(14), 7616; https://doi.org/10.3390/ijms25147616 - 11 Jul 2024
Cited by 14 | Viewed by 8506
Abstract
To date, more than 400 types of human papillomavirus (HPV) have been identified. Despite the creation of effective prophylactic vaccines against the most common genital HPVs, the viruses remain among the most prevalent pathogens found in humans. According to WHO data, they are [...] Read more.
To date, more than 400 types of human papillomavirus (HPV) have been identified. Despite the creation of effective prophylactic vaccines against the most common genital HPVs, the viruses remain among the most prevalent pathogens found in humans. According to WHO data, they are the cause of 5% of all cancers. Even more frequent are persistent and recurrent benign lesions such as genital and common warts. HPVs are resistant to many disinfectants and relatively unsusceptible to external conditions. There is still no drug available to inhibit viral replication, and treatment is based on removing lesions or stimulating the host immune system. This paper presents the systematics of HPV and the differences in HPV structure between different genetic types, lineages, and sublineages, based on the literature and GenBank data. We also present the pathogenesis of diseases caused by HPV, with a special focus on the role played by E6, E7, and other viral proteins in the development of benign and cancerous lesions. We discuss further prospects for the treatment of HPV infections, including, among others, substances that block the entry of HPV into cells, inhibitors of viral early proteins, and some substances of plant origin that inhibit viral replication, as well as new possibilities for therapeutic vaccines. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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22 pages, 4443 KiB  
Review
The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario
by Gioele Renzi, Fabrizio Carta and Claudiu T. Supuran
Int. J. Mol. Sci. 2023, 24(15), 12187; https://doi.org/10.3390/ijms241512187 - 29 Jul 2023
Cited by 6 | Viewed by 2372
Abstract
Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host genomes is a fundamental step in the replication cycle of all retroviruses. The highly conserved virus-encoded Integrase enzyme (IN; EC 2.7.7.49) catalyzes such a process by means of [...] Read more.
Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host genomes is a fundamental step in the replication cycle of all retroviruses. The highly conserved virus-encoded Integrase enzyme (IN; EC 2.7.7.49) catalyzes such a process by means of two consecutive reactions named 3′-processing (3-P) and strand transfer (ST). The Authors report and discuss the major discoveries and advances which mainly contributed to the development of Human Immunodeficiency Virus (HIV) -IN targeted inhibitors for therapeutic applications. All the knowledge accumulated over the years continues to serve as a valuable resource for the design and development of effective antiretroviral drugs. Full article
(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design 2.0)
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