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

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 30 June 2023 | Viewed by 8944

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Dr. Simone Brogi

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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; modeling 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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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. Viruses 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 2600 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 agents
in silico tools
emerging infectious diseases
viruses

Published Papers (10 papers)

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Research

Open AccessArticle

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

and

Abdelbasset A. Farahat

Viruses 2023, 15(5), 1171; https://doi.org/10.3390/v15051171 - 15 May 2023

Viewed by 530

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 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 10–12 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessCommunication

CXCR4 Recognition by L- and D-Peptides Containing the Full-Length V3 Loop of HIV-1 gp120

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Viruses 2023, 15(5), 1084; https://doi.org/10.3390/v15051084 - 28 Apr 2023

Viewed by 326

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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

Targeting the Human Influenza a Virus: The Methods, Limitations, and Pitfalls of Virtual Screening for Drug-like Candidates Including Scaffold Hopping and Compound Profiling

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

Viewed by 551

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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

Characterization of Anti-Poliovirus Compounds Isolated from Edible Plants

Minetaro Arita

and

Hiroyuki Fuchino

Viruses 2023, 15(4), 903; https://doi.org/10.3390/v15040903 - 31 Mar 2023

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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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

Discovery of Potential Inhibitors of SARS-CoV-2 Main Protease by a Transfer Learning Method

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Viruses 2023, 15(4), 891; https://doi.org/10.3390/v15040891 - 30 Mar 2023

Viewed by 712

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 (M^pro) 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 M^pro. 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-M^pro activities. Among all the selected hits, two compounds (gyssypol acetic acid and hyperoside) displayed inhibitory effects against M^pro 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

The Anti-Dengue Virus Peptide DV2 Inhibits Zika Virus Both In Vitro and In Vivo

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

Viewed by 577

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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

The Antiviral Compound PSP Inhibits HIV-1 Entry via PKR-Dependent Activation in Monocytic Cells

Eduardo Alvarez-Rivera

Madeline Rodríguez-Valentín

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Nawal M. Boukli

Viruses 2023, 15(3), 804; https://doi.org/10.3390/v15030804 - 22 Mar 2023

Viewed by 1466

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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

Non-Nucleoside Inhibitors Decrease Foot-and-Mouth Disease Virus Replication by Blocking the Viral 3D^pol

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

Viewed by 984

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 replication. Herein, we combined double virtual screenings and cell-based antiviral approaches to screen and identify potential inhibitors targeting FMDV RdRp (3D^pol). From 5596 compounds, the blind- followed by focus-docking filtered 21 candidates fitting in the 3D^pol 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 3D^pol activity in the cell-based 3D^pol inhibition assay with small IC50 values ranging from 0.8 nM to 0.22 µM without an effect on FMDV’s main protease, 3C^pro. The 3D^pol 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 3D^pol 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

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

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Viruses 2022, 14(12), 2760; https://doi.org/10.3390/v14122760 - 11 Dec 2022

Viewed by 1087

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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Open AccessArticle

Recent Information on Pan-Genotypic Direct-Acting Antiviral Agents for HCV in Chronic Kidney Disease

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Viruses 2022, 14(11), 2570; https://doi.org/10.3390/v14112570 - 20 Nov 2022

Viewed by 999

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 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

(This article belongs to the Special Issue Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Design, synthesis, charachterization, and in silico investigation of organic selenide tethered amidic acids as potential Mpro in-hibitors for the SARS-CoV-2 replication
Author: Shaaban
Highlights: New organic selenide tethered amidic acids were synthesized. Structures were elucidated using IR, 1H- and 13C-NMR, and MS . DFT, MEOP, and ADMET analysis were also performed. Molecular docking studies and molecular dynamics simulations were carried out.

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