Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation

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 (30 June 2023) | Viewed by 26392

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Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: in silico pharmacology; computational toxicology; computer-aided drug design; modelling and simulation; infectious diseases
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Dear Colleagues,

Infectious diseases continue to be one of the major causes of human and animal morbidity and mortality, accounting for ~20% of global death. Among them, viruses are responsible for about one-third of these deaths. During the last two decades, emerging and re-emerging viruses, such as the recent SARS-CoV-2 as well as related coronaviruses (SARS and MERS), avian influenza A (H5N1, H1N1, and H7N9) viruses, Zika virus, and enteroviruses, have posed significant global public health threats. Accordingly, the necessity to identify innovative antiviral agents, vaccines, novel therapeutic approaches based on drug repurposing, and novel strategies for early diagnosis and prevention are urgently needed, also considering the possibility of future outbreaks. In this scenario, computational procedures, including innovative machine learning approaches, could accelerate the discovery of effective antiviral agents and therapeutic strategies. To this end, we cordially invite researchers working in the antiviral drug discovery field, with a special focus on computer-aided drug discovery and molecular virology, to submit original research articles, short communications, and review articles related to the discovery of novel antiviral agents.

Dr. Simone Brogi
Guest Editor

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Keywords

  • antiviral agents
  • in silico tools
  • emerging infectious diseases
  • viruses

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Published Papers (16 papers)

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Editorial

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7 pages, 206 KiB  
Editorial
Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation
by Simone Brogi
Viruses 2023, 15(10), 2042; https://doi.org/10.3390/v15102042 - 02 Oct 2023
Cited by 1 | Viewed by 938
Abstract
Representing more than 20% of all deaths occurring worldwide, infectious diseases remain one of the main factors in both human and animal morbidity and mortality [...] Full article

Research

Jump to: Editorial, Review

14 pages, 5156 KiB  
Article
Targeting SARS-CoV-2 Macrodomain-1 to Restore the Innate Immune Response Using In Silico Screening of Medicinal Compounds and Free Energy Calculation Approaches
by Anwar Mohammad, Eman Alshawaf, Hossein Arefanian, Sulaiman K. Marafie, Abbas Khan, Dong-Qing Wei, Fahd Al-Mulla and Jehad Abubaker
Viruses 2023, 15(9), 1907; https://doi.org/10.3390/v15091907 - 12 Sep 2023
Cited by 1 | Viewed by 899
Abstract
Among the different drug targets of SARS-CoV-2, a multi-domain protein known as NSP3 is a critical element of the translational and replication machinery. The macrodomain-I, in particular, has been reported to have an essential role in the viral attack on the innate immune [...] Read more.
Among the different drug targets of SARS-CoV-2, a multi-domain protein known as NSP3 is a critical element of the translational and replication machinery. The macrodomain-I, in particular, has been reported to have an essential role in the viral attack on the innate immune response. In this study, we explore natural medicinal compounds and identify potential inhibitors to target the SARS-CoV-2–NSP3 macrodomain-I. Computational modeling and simulation tools were utilized to investigate the structural-dynamic properties using triplicates of 100 ns MD simulations. In addition, the MM/GBSA method was used to calculate the total binding free energy of each inhibitor bound to macrodomain-I. Two significant hits were identified: 3,5,7,4′-tetrahydroxyflavanone 3′-(4-hydroxybenzoic acid) and 2-hydroxy-3-O-beta-glucopyranosyl-benzoic acid. The structural-dynamic investigation of both compounds with macrodomain-I revealed stable dynamics and compact behavior. In addition, the total binding free energy for each complex demonstrated a robust binding affinity, of ΔG −61.98 ± 0.9 kcal/mol for Compound A, while for Compound B, the ΔG was −45.125 ± 2.8 kcal/mol, indicating the inhibitory potential of these compounds. In silico bioactivity and dissociation constant (KD) determination for both complexes further validated the inhibitory potency of each compound. In conclusion, the aforementioned natural products have the potential to inhibit NSP3, to directly rescue the host immune response. The current study provides the basis for novel drug development against SARS-CoV-2 and its variants. Full article
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16 pages, 3905 KiB  
Article
Antiviral Activity of an Indole-Type Compound Derived from Natural Products, Identified by Virtual Screening by Interaction on Dengue Virus NS5 Protein
by Leidy Lorena García-Ariza, Natalia González-Rivillas, Cindy Johanna Díaz-Aguirre, Cristian Rocha-Roa, Leonardo Padilla-Sanabria and Jhon Carlos Castaño-Osorio
Viruses 2023, 15(7), 1563; https://doi.org/10.3390/v15071563 - 17 Jul 2023
Cited by 4 | Viewed by 1432
Abstract
Dengue is an acute febrile illness caused by the Dengue virus (DENV), with a high number of cases worldwide. There is no available treatment that directly affects the virus or the viral cycle. The objective of this study was to identify a compound [...] Read more.
Dengue is an acute febrile illness caused by the Dengue virus (DENV), with a high number of cases worldwide. There is no available treatment that directly affects the virus or the viral cycle. The objective of this study was to identify a compound derived from natural products that interacts with the NS5 protein of the dengue virus through virtual screening and evaluate its in vitro antiviral effect on DENV-2. Molecular docking was performed on NS5 using AutoDock Vina software, and compounds with physicochemical and pharmacological properties of interest were selected. The preliminary antiviral effect was evaluated by the expression of the NS1 protein. The effect on viral genome replication and/or translation was determined by NS5 production using DENV-2 Huh-7 replicon through ELISA and viral RNA quantification using RT-qPCR. The in silico strategy proved effective in finding a compound (M78) with an indole-like structure and with an effect on the replication cycle of DENV-2. Treatment at 50 µM reduced the expression of the NS5 protein by 70% and decreased viral RNA by 1.7 times. M78 is involved in the replication and/or translation of the viral genome. Full article
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11 pages, 2563 KiB  
Communication
Applications of the Microscale Thermophoresis Binding Assay in COVID-19 Research
by Damian T. Nydegger, Jonai Pujol-Giménez, Palanivel Kandasamy, Bruno Vogt and Matthias A. Hediger
Viruses 2023, 15(7), 1432; https://doi.org/10.3390/v15071432 - 25 Jun 2023
Cited by 1 | Viewed by 1501
Abstract
As the COVID-19 pandemic progresses, new variants of SARS-CoV-2 continue to emerge. This underscores the need to develop optimized tools to study such variants, along with new coronaviruses that may arise in the future. Such tools will also be instrumental in the development [...] Read more.
As the COVID-19 pandemic progresses, new variants of SARS-CoV-2 continue to emerge. This underscores the need to develop optimized tools to study such variants, along with new coronaviruses that may arise in the future. Such tools will also be instrumental in the development of new antiviral drugs. Here, we introduce microscale thermophoresis (MST) as a reliable and versatile tool for coronavirus research, which we demonstrate through three different applications described in this report: (1) binding of the SARS-CoV-2 spike receptor binding domain (RBD) to peptides as a strategy to prevent virus entry, (2) binding of the RBD to the viral receptor ACE2, and (3) binding of the RBD to ACE2 in complex with the amino acid transporter SLC6A20/SIT1 or its allelic variant rs61731475 (p.Ile529Val). Our results demonstrate that MST is a highly precise approach to studying protein–protein and/or protein–ligand interactions in coronavirus research, making it an ideal tool for studying viral variants and developing antiviral agents. Moreover, as shown in our results, a unique advantage of the MST assay over other available binding assays is the ability to measure interactions with membrane proteins in their near-native plasma membrane environment. Full article
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11 pages, 1676 KiB  
Article
Anticoronavirus Evaluation of Antimicrobial Diterpenoids: Application of New Ferruginol Analogues
by Mihayl Varbanov, Stéphanie Philippot and Miguel A. González-Cardenete
Viruses 2023, 15(6), 1342; https://doi.org/10.3390/v15061342 - 09 Jun 2023
Cited by 2 | Viewed by 1185
Abstract
The abietane diterpene (+)-ferruginol (1), like other natural and semisynthetic abietanes, is distinguished for its interesting pharmacological properties such as antimicrobial activity, including antiviral. In this study, selected C18-functionalized semisynthetic abietanes prepared from the commercially available (+)-dehydroabietylamine or methyl dehydroabietate were [...] Read more.
The abietane diterpene (+)-ferruginol (1), like other natural and semisynthetic abietanes, is distinguished for its interesting pharmacological properties such as antimicrobial activity, including antiviral. In this study, selected C18-functionalized semisynthetic abietanes prepared from the commercially available (+)-dehydroabietylamine or methyl dehydroabietate were tested in vitro against human coronavirus 229E (HCoV-229E). As a result, a new ferruginol analogue caused a relevant reduction in virus titer as well as the inhibition of a cytopathic effect. A toxicity prediction based on in silico analysis was also performed as well as an estimation of bioavailability. This work demonstrates the antimicrobial and specifically antiviral activity of two tested compounds, making these molecules interesting for the development of new antivirals. Full article
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19 pages, 2064 KiB  
Article
In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
by Ahmed H. E. Hassan, Selwan M. El-Sayed, Mizuki Yamamoto, Jin Gohda, Takehisa Matsumoto, Mikako Shirouzu, Jun-ichiro Inoue, Yasushi Kawaguchi, Reem M. A. Mansour, Abtin Anvari and Abdelbasset A. Farahat
Viruses 2023, 15(5), 1171; https://doi.org/10.3390/v15051171 - 15 May 2023
Cited by 3 | Viewed by 1760
Abstract
Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent [...] Read more.
Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 1012 triggered potential TMPRSS2 inhibition with low micromolar IC50 concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC50 value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses. Full article
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9 pages, 2820 KiB  
Communication
CXCR4 Recognition by L- and D-Peptides Containing the Full-Length V3 Loop of HIV-1 gp120
by Ruohan Zhu, Xiaohong Sang, Jiao Zhou, Qian Meng, Lina S. M. Huang, Yan Xu, Jing An and Ziwei Huang
Viruses 2023, 15(5), 1084; https://doi.org/10.3390/v15051084 - 28 Apr 2023
Cited by 1 | Viewed by 1001
Abstract
Human immunodeficiency virus-1 (HIV-1) recognizes one of its principal coreceptors, CXC chemokine receptor 4 (CXCR4), on the host cell via the third variable loop (V3 loop) of HIV-1 envelope glycoprotein gp120 during the viral entry process. Here, the mechanism of the molecular recognition [...] Read more.
Human immunodeficiency virus-1 (HIV-1) recognizes one of its principal coreceptors, CXC chemokine receptor 4 (CXCR4), on the host cell via the third variable loop (V3 loop) of HIV-1 envelope glycoprotein gp120 during the viral entry process. Here, the mechanism of the molecular recognition of HIV-1 gp120 V3 loop by coreceptor CXCR4 was probed by synthetic peptides containing the full-length V3 loop. The two ends of the V3 loop were covalently linked by a disulfide bond to form a cyclic peptide with better conformational integrity. In addition, to probe the effect of the changed side-chain conformations of the peptide on CXCR4 recognition, an all-D-amino acid analog of the L-V3 loop peptide was generated. Both of these cyclic L- and D-V3 loop peptides displayed comparable binding recognition to the CXCR4 receptor, but not to another chemokine receptor, CCR5, suggesting their selective interactions with CXCR4. Molecular modeling studies revealed the important roles played by many negative-charged Asp and Glu residues on CXCR4 that probably engaged in favorable electrostatic interactions with the positive-charged Arg residues present in these peptides. These results support the notion that the HIV-1 gp120 V3 loop-CXCR4 interface is flexible for ligands of different chiralities, which might be relevant in terms of the ability of the virus to retain coreceptor recognition despite the mutations at the V3 loop. Full article
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18 pages, 3361 KiB  
Article
Targeting the Human Influenza a Virus: The Methods, Limitations, and Pitfalls of Virtual Screening for Drug-like Candidates Including Scaffold Hopping and Compound Profiling
by Thomas Scior, Karina Cuanalo-Contreras, Angel A. Islas and Ygnacio Martinez-Laguna
Viruses 2023, 15(5), 1056; https://doi.org/10.3390/v15051056 - 26 Apr 2023
Cited by 1 | Viewed by 1378
Abstract
In this study, we describe the input data and processing steps to find antiviral lead compounds by a virtual screen. Two-dimensional and three-dimensional filters were designed based on the X-ray crystallographic structures of viral neuraminidase co-crystallized with substrate sialic acid, substrate-like DANA, and [...] Read more.
In this study, we describe the input data and processing steps to find antiviral lead compounds by a virtual screen. Two-dimensional and three-dimensional filters were designed based on the X-ray crystallographic structures of viral neuraminidase co-crystallized with substrate sialic acid, substrate-like DANA, and four inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir). As a result, ligand–receptor interactions were modeled, and those necessary for binding were utilized as screen filters. Prospective virtual screening (VS) was carried out in a virtual chemical library of over half a million small organic substances. Orderly filtered moieties were investigated based on 2D- and 3D-predicted binding fingerprints disregarding the “rule-of-five” for drug likeness, and followed by docking and ADMET profiling. Two-dimensional and three-dimensional screening were supervised after enriching the dataset with known reference drugs and decoys. All 2D, 3D, and 4D procedures were calibrated before execution, and were then validated. Presently, two top-ranked substances underwent successful patent filing. In addition, the study demonstrates how to work around reported VS pitfalls in detail. Full article
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14 pages, 2057 KiB  
Article
Characterization of Anti-Poliovirus Compounds Isolated from Edible Plants
by Minetaro Arita and Hiroyuki Fuchino
Viruses 2023, 15(4), 903; https://doi.org/10.3390/v15040903 - 31 Mar 2023
Cited by 1 | Viewed by 1503
Abstract
Poliovirus (PV) is the causative agent of poliomyelitis and is a target of the global eradication programs of the World Health Organization (WHO). After eradication of type 2 and 3 wild-type PVs, vaccine-derived PV remains a substantial threat against the eradication as well [...] Read more.
Poliovirus (PV) is the causative agent of poliomyelitis and is a target of the global eradication programs of the World Health Organization (WHO). After eradication of type 2 and 3 wild-type PVs, vaccine-derived PV remains a substantial threat against the eradication as well as type 1 wild-type PV. Antivirals could serve as an effective means to suppress the outbreak; however, no anti-PV drugs have been approved at present. Here, we screened for effective anti-PV compounds in a library of edible plant extracts (a total of 6032 extracts). We found anti-PV activity in the extracts of seven different plant species. We isolated chrysophanol and vanicoside B (VCB) as the identities of the anti-PV activities of the extracts of Rheum rhaponticum and Fallopia sachalinensis, respectively. VCB targeted the host PI4KB/OSBP pathway for its anti-PV activity (EC50 = 9.2 μM) with an inhibitory effect on in vitro PI4KB activity (IC50 = 5.0 μM). This work offers new insights into the anti-PV activity in edible plants that may serve as potent antivirals for PV infection. Full article
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14 pages, 14043 KiB  
Article
Discovery of Potential Inhibitors of SARS-CoV-2 Main Protease by a Transfer Learning Method
by Huijun Zhang, Boqiang Liang, Xiaohong Sang, Jing An and Ziwei Huang
Viruses 2023, 15(4), 891; https://doi.org/10.3390/v15040891 - 30 Mar 2023
Cited by 3 | Viewed by 1778
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 remains a global public health threat and has prompted the development of antiviral therapies. Artificial intelligence may be one of the strategies to facilitate drug development for emerging and re-emerging diseases. The main protease (Mpro) [...] Read more.
The COVID-19 pandemic caused by SARS-CoV-2 remains a global public health threat and has prompted the development of antiviral therapies. Artificial intelligence may be one of the strategies to facilitate drug development for emerging and re-emerging diseases. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target due to its essential role in the virus life cycle and high conservation among SARS-CoVs. In this study, we used a data augmentation method to boost transfer learning model performance in screening for potential inhibitors of SARS-CoV-2 Mpro. This method appeared to outperform graph convolution neural network, random forest and Chemprop on an external test set. The fine-tuned model was used to screen for a natural compound library and a de novo generated compound library. By combination with other in silico analysis methods, a total of 27 compounds were selected for experimental validation of anti-Mpro activities. Among all the selected hits, two compounds (gyssypol acetic acid and hyperoside) displayed inhibitory effects against Mpro with IC50 values of 67.6 μM and 235.8 μM, respectively. The results obtained in this study may suggest an effective strategy of discovering potential therapeutic leads for SARS-CoV-2 and other coronaviruses. Full article
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11 pages, 1834 KiB  
Article
The Anti-Dengue Virus Peptide DV2 Inhibits Zika Virus Both In Vitro and In Vivo
by Maria Fernanda de Castro-Amarante, Samuel Santos Pereira, Lennon Ramos Pereira, Lucas Souza Santos, Alexia Adrianne Venceslau-Carvalho, Eduardo Gimenes Martins, Andrea Balan and Luís Carlos de Souza Ferreira
Viruses 2023, 15(4), 839; https://doi.org/10.3390/v15040839 - 25 Mar 2023
Cited by 2 | Viewed by 1482
Abstract
The C-terminal portion of the E protein, known as stem, is conserved among flaviviruses and is an important target to peptide-based antiviral strategies. Since the dengue (DENV) and Zika (ZIKV) viruses share sequences in the stem region, in this study we evaluated the [...] Read more.
The C-terminal portion of the E protein, known as stem, is conserved among flaviviruses and is an important target to peptide-based antiviral strategies. Since the dengue (DENV) and Zika (ZIKV) viruses share sequences in the stem region, in this study we evaluated the cross-inhibition of ZIKV by the stem-based DV2 peptide (419–447), which was previously described to inhibit all DENV serotypes. Thus, the anti-ZIKV effects induced by treatments with the DV2 peptide were tested in both in vitro and in vivo conditions. Molecular modeling approaches have demonstrated that the DV2 peptide interacts with amino acid residues exposed on the surface of pre- and postfusion forms of the ZIKA envelope (E) protein. The peptide did not have any significant cytotoxic effects on eukaryotic cells but efficiently inhibited ZIKV infectivity in cultivated Vero cells. In addition, the DV2 peptide reduced morbidity and mortality in mice subjected to lethal challenges with a ZIKV strain isolated in Brazil. Taken together, the present results support the therapeutic potential of the DV2 peptide against ZIKV infections and open perspectives for the development and clinical testing of anti-flavivirus treatments based on synthetic stem-based peptides. Full article
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24 pages, 3647 KiB  
Article
The Antiviral Compound PSP Inhibits HIV-1 Entry via PKR-Dependent Activation in Monocytic Cells
by Eduardo Alvarez-Rivera, Madeline Rodríguez-Valentín and Nawal M. Boukli
Viruses 2023, 15(3), 804; https://doi.org/10.3390/v15030804 - 22 Mar 2023
Cited by 3 | Viewed by 2915
Abstract
Actin depolymerization factor (ADF) cofilin-1 is a key cytoskeleton component that serves to lessen cortical actin. HIV-1 manipulates cofilin-1 regulation as a pre- and post-entry requisite. Disruption of ADF signaling is associated with denial of entry. The unfolded protein response (UPR) marker Inositol-Requiring [...] Read more.
Actin depolymerization factor (ADF) cofilin-1 is a key cytoskeleton component that serves to lessen cortical actin. HIV-1 manipulates cofilin-1 regulation as a pre- and post-entry requisite. Disruption of ADF signaling is associated with denial of entry. The unfolded protein response (UPR) marker Inositol-Requiring Enzyme-1α (IRE1α) and interferon-induced protein (IFN-IP) double-stranded RNA- activated protein kinase (PKR) are reported to overlap with actin components. In our published findings, Coriolus versicolor bioactive extract polysaccharide peptide (PSP) has demonstrated anti-HIV replicative properties in THP1 monocytic cells. However, its involvement towards viral infectivity has not been elucidated before. In the present study, we examined the roles of PKR and IRE1α in cofilin-1 phosphorylation and its HIV-1 restrictive roles in THP1. HIV-1 p24 antigen was measured through infected supernatant to determine PSP’s restrictive potential. Quantitative proteomics was performed to analyze cytoskeletal and UPR regulators. PKR, IRE1α, and cofilin-1 biomarkers were measured through immunoblots. Validation of key proteome markers was done through RT-qPCR. PKR/IRE1α inhibitors were used to validate viral entry and cofilin-1 phosphorylation through Western blots. Our findings show that PSP treatment before infection leads to an overall lower infectivity. Additionally, PKR and IRE1α show to be key regulators in cofilin-1 phosphorylation and viral restriction. Full article
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17 pages, 2982 KiB  
Article
Non-Nucleoside Inhibitors Decrease Foot-and-Mouth Disease Virus Replication by Blocking the Viral 3Dpol
by Sirin Theerawatanasirikul, Ploypailin Semkum, Varanya Lueangaramkul, Penpitcha Chankeeree, Nattarat Thangthamniyom and Porntippa Lekcharoensuk
Viruses 2023, 15(1), 124; https://doi.org/10.3390/v15010124 - 30 Dec 2022
Cited by 3 | Viewed by 1733
Abstract
Foot-and-mouth disease virus (FMDV), an economically important pathogen of cloven-hoofed livestock, is a positive-sense, single-stranded RNA virus classified in the Picornaviridae family. RNA-dependent RNA polymerase (RdRp) of RNA viruses is highly conserved. Compounds that bind to the RdRp active site can block viral [...] Read more.
Foot-and-mouth disease virus (FMDV), an economically important pathogen of cloven-hoofed livestock, is a positive-sense, single-stranded RNA virus classified in the Picornaviridae family. RNA-dependent RNA polymerase (RdRp) of RNA viruses is highly conserved. Compounds that bind to the RdRp active site can block viral replication. Herein, we combined double virtual screenings and cell-based antiviral approaches to screen and identify potential inhibitors targeting FMDV RdRp (3Dpol). From 5596 compounds, the blind- followed by focus-docking filtered 21 candidates fitting in the 3Dpol active sites. Using the BHK-21 cell-based assay, we found that four compounds—NSC217697 (quinoline), NSC670283 (spiro compound), NSC292567 (nigericin), and NSC65850—demonstrated dose-dependent antiviral actions in vitro with the EC50 ranging from 0.78 to 3.49 µM. These compounds could significantly block FMDV 3Dpol activity in the cell-based 3Dpol inhibition assay with small IC50 values ranging from 0.8 nM to 0.22 µM without an effect on FMDV’s main protease, 3Cpro. The 3Dpol inhibition activities of the compounds were consistent with the decreased viral load and negative-stranded RNA production in a dose-dependent manner. Conclusively, we have identified potential FMDV 3Dpol inhibitors that bound within the enzyme active sites and blocked viral replication. These compounds might be beneficial for FMDV or other picornavirus treatment. Full article
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20 pages, 6060 KiB  
Article
In Vitro and Pre-Clinical Evaluation of Locally Isolated Phages, vB_Pae_SMP1 and vB_Pae_SMP5, Formulated as Hydrogels against Carbapenem-Resistant Pseudomonas aeruginosa
by Samar S. Mabrouk, Ghada R. Abdellatif, Ahmed S. Abu Zaid, Ramy K. Aziz and Khaled M. Aboshanab
Viruses 2022, 14(12), 2760; https://doi.org/10.3390/v14122760 - 11 Dec 2022
Cited by 4 | Viewed by 1980
Abstract
The inadequate therapeutic opportunities associated with carbapenem-resistant Pseudomonas aeruginosa (CRPA) clinical isolates impose a search for innovative strategies. Therefore, our study aimed to characterize and evaluate two locally isolated phages formulated in a hydrogel, both in vitro and in vivo, against CRPA clinical [...] Read more.
The inadequate therapeutic opportunities associated with carbapenem-resistant Pseudomonas aeruginosa (CRPA) clinical isolates impose a search for innovative strategies. Therefore, our study aimed to characterize and evaluate two locally isolated phages formulated in a hydrogel, both in vitro and in vivo, against CRPA clinical isolates. The two phages were characterized by genomic, microscopic, phenotypic characterization, genomic analysis, in vitro and in vivo analysis in a Pseudomonas aeruginosa-infected skin thermal injury rat model. The two siphoviruses belong to class Caudovirectes and were named vB_Pae_SMP1 and vB_Pae_SMP5. Each phage had an icosahedral head of 60 ± 5 nm and a flexible, non-contractile tail of 170 ± 5 nm long, while vB_Pae_SMP5 had an additional base plate containing a 35 nm fiber observed at the end of the tail. The hydrogel was prepared by mixing 5% w/v carboxymethylcellulose (CMC) into the CRPA propagated phage lysate containing phage titer 108 PFU/mL, pH of 7.7, and a spreadability coefficient of 25. The groups were treated with either Phage vB_Pae_SMP1, vB_Pae_SMP5, or a two-phage cocktail hydrogel cellular subepidermal granulation tissues with abundant records of fibroblastic activity and mixed inflammatory cell infiltrates and showed 17.2%, 25.8%, and 22.2% records of dermal mature collagen fibers, respectively. In conclusion, phage vB_Pae_SMP1 or vB_Pae_SMP5, or the two-phage cocktails formulated as hydrogels, were able to manage the infection of CRPA in burn wounds, and promoted healing at the injury site, as evidenced by the histopathological examination, as well as a decrease in animal mortality rate. Therefore, these phage formulae can be considered promising for clinical investigation in humans for the management of CRPA-associated skin infections. Full article
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12 pages, 571 KiB  
Article
Recent Information on Pan-Genotypic Direct-Acting Antiviral Agents for HCV in Chronic Kidney Disease
by Fabrizio Fabrizi, Federica Tripodi, Roberta Cerutti, Luca Nardelli, Carlo M. Alfieri, Maria F. Donato and Giuseppe Castellano
Viruses 2022, 14(11), 2570; https://doi.org/10.3390/v14112570 - 20 Nov 2022
Cited by 2 | Viewed by 1600
Abstract
Background: Hepatitis C virus (HCV) is still common in patients with chronic kidney disease. It has been recently discovered that chronic HCV is a risk factor for increased incidence of CKD in the adult general population. According to a systematic review with a [...] Read more.
Background: Hepatitis C virus (HCV) is still common in patients with chronic kidney disease. It has been recently discovered that chronic HCV is a risk factor for increased incidence of CKD in the adult general population. According to a systematic review with a meta-analysis of clinical studies, pooling results of longitudinal studies (n = 2,299,134 unique patients) demonstrated an association between positive anti-HCV serologic status and increased incidence of CKD; the summary estimate for adjusted HR across the surveys was 1.54 (95% CI, 1.26; 1.87), (p < 0.0001). The introduction of direct-acting antiviral drugs (DAAs) has caused a paradigm shift in the management of HCV infection; recent guidelines recommend pan-genotypic drugs (i.e., drugs effective on all HCV genotypes) as the first-choice therapy for HCV, and these promise to be effective and safe even in the context of chronic kidney disease. Aim: The purpose of this narrative review is to show the most important data on pan-genotypic DAAs in advanced CKD (CKD stage 4/5). Methods: We recruited studies by electronic databases and grey literature. Numerous key-words (‘Hepatitis C’ AND ‘Chronic kidney disease’ AND ‘Pan-genotypic agents’, among others) were adopted. Results: The most important pan-genotypic combinations for HCV in advanced CKD are glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL). Two clinical trials (EXPEDITION-4 and EXPEDITION-5) and some ‘real-world’ studies (n = 6) reported that GLE/PIB combinations in CKD stage 4/5 gave SVR12 rates ranging between 86 and 99%. We retrieved clinical trials (n = 1) and ‘real life’ studies (n = 6) showing the performance of SOF/VEL; according to our pooled analysis, the summary estimate of SVR rate was 100% in studies adopting SOF/VEL antiviral combinations. The drop-out rate (due to AEs) in patients on SOF/VEL ranged between 0 and 4.8%. Conclusions: Pan-genotypic combinations, such as GLE/PIB and SOF/VEL, appear effective and safe for HCV in advanced CKD, even if a limited number of studies with small sample sizes currently exist on this issue. Studies are under way to assess whether successful antiviral therapy with DAAs will translate into better survival in patients with advanced CKD. Full article
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Review

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Review
Structural and Synthetic Aspects of Small Ring Oxa- and Aza-Heterocyclic Ring Systems as Antiviral Activities
by Sibasish Manna, Koushik Das, Sougata Santra, Emily V. Nosova, Grigory V. Zyryanov and Sandipan Halder
Viruses 2023, 15(9), 1826; https://doi.org/10.3390/v15091826 - 28 Aug 2023
Cited by 1 | Viewed by 1630
Abstract
Antiviral properties of different oxa- and aza-heterocycles are identified and properly correlated with their structural features and discussed in this review article. The primary objective is to explore the activity of such ring systems as antiviral agents, as well as their synthetic routes [...] Read more.
Antiviral properties of different oxa- and aza-heterocycles are identified and properly correlated with their structural features and discussed in this review article. The primary objective is to explore the activity of such ring systems as antiviral agents, as well as their synthetic routes and biological significance. Eventually, the structure–activity relationship (SAR) of the heterocyclic compounds, along with their salient characteristics are exhibited to build a suitable platform for medicinal chemists and biotechnologists. The synergistic conclusions are extremely important for the introduction of a newer tool for the future drug discovery program. Full article
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