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Antiviral Agents for RNA-Virus Infection
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Antiviral Agents for RNA-Virus Infection

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 54522

Special Issue Editor

Dr. Koh Fujinaga

E-Mail Website
Guest Editor
Department of Medicine, University of California, San Francisco, CA 94143-0703, USA
Interests: mechanisms of eukaryotic trancription elongation; HIV latency and reactivation; cellular innate immunity; RNA-dependent RNA polymerases.

Special Issue Information

Dear Colleagues,

As we all know, the 2019/2020 pandemic of COVID-19/SARS-CoV-2 has severely affected our life and economy. From the beginning, human history has been filled with battles against pathogens. In recent years, RNA-viruses such as influenza virus, poliovirus, HIV, and coronavirus have rapidly spread among people globally, threatening our civilization. Except for those that use DNA intermediates such as HIV, a common feature of RNA-viruses is that viruses encode their own RNA polymerase for replication, which is an excellent target for antiviral agents. In this special issue of Molecules, we will discuss our recent approaches to develop antiviral agents against RNA-viruses targeting various steps in viral life cycles, which will provide clues to prepare for current and future pandemics of emerging RNA viral infections. 

Dr. Koh Fujinaga
Guest Editor

Manuscript Submission Information

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Keywords

  • antiviral agents
  • RNA-viruses
  • SARS-CoV
  • COVID-19
  • Zika Virus
  • Ebola Virus
  • West Nile Virus
  • HCV
  • Dengue Virus
  • Rift Valley Virus
  • Yellow Fever Virus
  • Emerging Diseases
  • HIV
  • Influenza Virus
  • RNA-dependent RNA polymerase

Published Papers (18 papers)

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Research

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15 pages, 2645 KiB  
Article
Acetyl-CoA Carboxylase (ACC) Inhibitor, CP640186, Effectively Inhibited Dengue Virus (DENV) Infection via Regulating ACC Phosphorylation
by Wenyu Wu, Ruilin Chen, Yuanda Wan, Liren Li, Jiajia Han, Qiyun Lei, Zhipeng Chen, Shuwen Liu and Xingang Yao
Molecules 2022, 27(23), 8583; https://doi.org/10.3390/molecules27238583 - 5 Dec 2022
Viewed by 1705
Abstract
Dengue fever is the most common mosquito-borne viral disease and is caused by the dengue virus (DENV). There is still a lack of efficient drugs against DENV infection, so it is urgent to develop new inhibitors for future clinical use. Our previous research [...] Read more.
Dengue fever is the most common mosquito-borne viral disease and is caused by the dengue virus (DENV). There is still a lack of efficient drugs against DENV infection, so it is urgent to develop new inhibitors for future clinical use. Our previous research indicated the role of VEGFR2/AMPK in regulating cellular metabolism during DENV infection, while acetyl-CoA carboxylase (ACC) is located downstream of AMPK and plays a crucial role in mediating cellular lipid synthesis; therefore, we speculated that an ACC inhibitor could serve as an antiviral agent against DENV. Luckily, we found that CP640186, a reported noncompetitive ACC inhibitor, significantly inhibited DENV proliferation, and CP640186 clearly reduced DENV2 proliferation at an early stage with an EC50 of 0.50 μM. A mechanism study indicated that CP640186 inhibited ACC activation and destroyed the cellular lipid environment for viral proliferation. In the DENV2 infection mice model, oral CP640186 administration (10 mg/kg/day) significantly improved the mice survival rate after DENV2 infection. In summary, our research suggests that lipid synthesis plays an important role during DENV2 proliferation and indicates that CP640186 is a promising drug candidate against DNEV2 in the future. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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20 pages, 5214 KiB  
Article
Honokiol and Alpha-Mangostin Inhibit Mayaro Virus Replication through Different Mechanisms
by Patricia Valdés-Torres, Dalkiria Campos, Madhvi Bhakta, Paola Elaine Galán-Jurado, Armando A. Durant-Archibold and José González-Santamaría
Molecules 2022, 27(21), 7362; https://doi.org/10.3390/molecules27217362 - 29 Oct 2022
Cited by 3 | Viewed by 2120
Abstract
Mayaro virus (MAYV) is an emerging arbovirus with an increasing circulation across the Americas. In the present study, we evaluated the potential antiviral activity of the following natural compounds against MAYV and other arboviruses: Sanguinarine, (R)-Shikonin, Fisetin, Honokiol, Tanshinone IIA, and α-Mangostin. Sanguinarine [...] Read more.
Mayaro virus (MAYV) is an emerging arbovirus with an increasing circulation across the Americas. In the present study, we evaluated the potential antiviral activity of the following natural compounds against MAYV and other arboviruses: Sanguinarine, (R)-Shikonin, Fisetin, Honokiol, Tanshinone IIA, and α-Mangostin. Sanguinarine and Shikonin showed significant cytotoxicity, whereas Fisetin, Honokiol, Tanshinone IIA, and α-Mangostin were well tolerated in all the cell lines tested. Honokiol and α-Mangostin treatment protected Vero-E6 cells against MAYV-induced damage and resulted in a dose-dependent reduction in viral progeny yields for each of the MAYV strains and human cell lines assessed. These compounds also reduced MAYV viral RNA replication in HeLa cells. In addition, Honokiol and α-Mangostin disrupted MAYV infection at different stages of the virus life cycle. Moreover, Honokiol and α-Mangostin decreased Una, Chikungunya, and Zika viral titers and downmodulated the expression of E1 and nsP1 viral proteins from MAYV, Una, and Chikungunya. Finally, in Honokiol- and α-Mangostin-treated HeLa cells, we observed an upregulation in the expression of type I interferon and specific interferon-stimulated genes, including IFNα, IFNβ, MxA, ISG15, OAS2, MDA-5, TNFα, and IL-1β, which may promote an antiviral cellular state. Our results indicate that Honokiol and α-Mangostin present potential broad-spectrum activity against different arboviruses through different mechanisms. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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11 pages, 1287 KiB  
Article
Antiviral Effect of Bovine Lactoferrin against Enterovirus E
by Małgorzata Wróbel, Joanna Małaczewska and Edyta Kaczorek-Łukowska
Molecules 2022, 27(17), 5569; https://doi.org/10.3390/molecules27175569 - 29 Aug 2022
Cited by 2 | Viewed by 1665
Abstract
Enterovirus E (EV-E), a representative of the Picornaviridae family, endemically affects cattle across the world, typically causing subclinical infections. However, under favorable conditions, severe or fatal disorders of the respiratory, digestive, and reproductive systems may develop. There is no specific treatment for enterovirus [...] Read more.
Enterovirus E (EV-E), a representative of the Picornaviridae family, endemically affects cattle across the world, typically causing subclinical infections. However, under favorable conditions, severe or fatal disorders of the respiratory, digestive, and reproductive systems may develop. There is no specific treatment for enterovirus infections in humans or animals, and only symptomatic treatment is available. The aim of this study was to determine the in vitro antiviral effect of bovine lactoferrin (bLF) against enterovirus E using virucidal, cytopathic effect inhibition, and viral yield reduction assays in MDBK cells. The influence of lactoferrin on the intracellular viral RNA level was also determined. Surprisingly, lactoferrin did not have a protective effect on cells, although it inhibited the replication of the virus during the adsorption and post-adsorption stages (viral titres reduced by 1–1.1 log). Additionally, a decrease in the viral RNA level in cells (by up to 75%) was observed. More detailed studies are needed to determine the mechanism of bovine lactoferrin effect on enterovirus E. However, this highly biocompatible protein ensures some degree of protection against infection by bovine enterovirus, which is particularly important for young animals that receive this protein in their mother’s milk. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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12 pages, 1324 KiB  
Article
The Efficacy of Aprotinin Combinations with Selected Antiviral Drugs in Mouse Models of Influenza Pneumonia and Coronavirus Infection Caused by SARS-CoV-2
by Andrey A. Ivashchenko, Bogdan A. Zagribelnyy, Yan A. Ivanenkov, Ilya A. Ivashchenko, Ruben N. Karapetian, Dmitry V. Kravchenko, Nikolay P. Savchuk, Elena V. Yakubova and Alexandre V. Ivachtchenko
Molecules 2022, 27(15), 4975; https://doi.org/10.3390/molecules27154975 - 5 Aug 2022
Cited by 1 | Viewed by 1808
Abstract
The efficacy of aprotinin combinations with selected antiviral-drugs treatment of influenza virus and coronavirus (SARS-CoV-2) infection was studied in mice models of influenza pneumonia and COVID-19. The high efficacy of the combinations in reducing virus titer in lungs and body weight loss and [...] Read more.
The efficacy of aprotinin combinations with selected antiviral-drugs treatment of influenza virus and coronavirus (SARS-CoV-2) infection was studied in mice models of influenza pneumonia and COVID-19. The high efficacy of the combinations in reducing virus titer in lungs and body weight loss and in increasing the survival rate were demonstrated. This preclinical study can be considered a confirmatory step before introducing the combinations into clinical assessment. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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17 pages, 6739 KiB  
Article
Identification of 3-Oxindole Derivatives as Small Molecule HIV-1 Inhibitors Targeting Tat-Mediated Viral Transcription
by Dong-Eun Kim, Young Hyun Shin, Jung-Eun Cho, Subeen Myung, Hong Gi Kim, Kyung-Chang Kim, Chul Min Park and Cheol-Hee Yoon
Molecules 2022, 27(15), 4921; https://doi.org/10.3390/molecules27154921 - 2 Aug 2022
Cited by 1 | Viewed by 1599
Abstract
The heterocyclic indole structure has been shown to be one of the most promising scaffolds, offering various medicinal advantages from its wide range of biological activity. Nonetheless, the significance of 3-oxindole has been less known. In this study, a series of novel 3-oxindole-2-carboxylates [...] Read more.
The heterocyclic indole structure has been shown to be one of the most promising scaffolds, offering various medicinal advantages from its wide range of biological activity. Nonetheless, the significance of 3-oxindole has been less known. In this study, a series of novel 3-oxindole-2-carboxylates were synthesized and their antiviral activity against human immunodeficiency virus-1 (HIV-1) infection was evaluated. Among these, methyl (E)-2-(3-chloroallyl)-4,6-dimethyl-one (6f) exhibited the most potent inhibitory effect on HIV-1 infection, with a half-maximal inhibitory concentration (IC50) of 0.4578 μM but without severe cytotoxicity (selectivity index (SI) = 111.37). The inhibitory effect of these compounds on HIV-1 infection was concordant with their inhibitory effect on the viral replication cycle. Mode-of-action studies have shown that these prominent derivatives specifically inhibited the Tat-mediated viral transcription on the HIV-1 LTR promoter instead of reverse transcription or integration. Overall, our findings indicate that 3-oxindole derivatives could be useful as a potent scaffold for the development of a new class of anti-HIV-1 agents. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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33 pages, 5765 KiB  
Article
Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir
by Aaminat Qureshi, Louise A. Ouattara, Naglaa Salem El-Sayed, Amita Verma, Gustavo F. Doncel, Muhammad Iqbal Choudhary, Hina Siddiqui and Keykavous Parang
Molecules 2022, 27(14), 4447; https://doi.org/10.3390/molecules27144447 - 12 Jul 2022
Cited by 2 | Viewed by 2221
Abstract
The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the [...] Read more.
The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV (1) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate (69), pentanolyl ester alanine phosphonamidate with phenol oleate (62), and butanolyl ester alanine phosphonamidate with naphthol oleate (87) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97–99% inhibition) at 10–100 ng/mL but was more potent than TAF when compared at molar concentration. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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11 pages, 2439 KiB  
Article
In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
by Shuo Wang, Xuexun Fang and Ye Wang
Molecules 2022, 27(13), 4210; https://doi.org/10.3390/molecules27134210 - 30 Jun 2022
Cited by 7 | Viewed by 1727
Abstract
COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that [...] Read more.
COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein–ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein–ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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14 pages, 4503 KiB  
Article
Synthesis and Antiviral Properties against SARS-CoV-2 of Epoxybenzooxocino[4,3-b]Pyridine Derivatives
by Alena L. Stalinskaya, Nadezhda V. Martynenko, Zarina T. Shulgau, Alexandr V. Shustov, Viktoriya V. Keyer and Ivan V. Kulakov
Molecules 2022, 27(12), 3701; https://doi.org/10.3390/molecules27123701 - 9 Jun 2022
Cited by 8 | Viewed by 2195
Abstract
The COVID-19 pandemic is ongoing as of mid-2022 and requires the development of new therapeutic drugs, because the existing clinically approved drugs are limited. In this work, seven derivatives of epoxybenzooxocinopyridine were synthesized and tested for the ability to inhibit the replication of [...] Read more.
The COVID-19 pandemic is ongoing as of mid-2022 and requires the development of new therapeutic drugs, because the existing clinically approved drugs are limited. In this work, seven derivatives of epoxybenzooxocinopyridine were synthesized and tested for the ability to inhibit the replication of the SARS-CoV-2 virus in cell cultures. Among the described compounds, six were not able to suppress the SARS-CoV-2 virus’ replication. One compound, which is a derivative of epoxybenzooxocinopyridine with an attached side group of 3,4-dihydroquinoxalin-2-one, demonstrated antiviral activity comparable to that of one pharmaceutical drug. The described compound is a prospective lead substance, because the half-maximal effective concentration is 2.23 μg/μL, which is within a pharmacologically achievable range. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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17 pages, 1280 KiB  
Article
Synthesis and Biological Evaluation of 5′-O-Fatty Acyl Ester Derivatives of 3′-Fluoro-2′,3′-dideoxythymidine as Potential Anti-HIV Microbicides
by Hitesh K. Agarwal, Bhupender S. Chhikara, Guofeng Ye, Sitaram Bhavaraju, Ajay Dixit, Anil Kumar, Gustavo F. Doncel and Keykavous Parang
Molecules 2022, 27(10), 3352; https://doi.org/10.3390/molecules27103352 - 23 May 2022
Cited by 1 | Viewed by 2766
Abstract
A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), [...] Read more.
A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), 5′-O-(12-azidododecanoyl) (5), 5′-O-myristoyl (6), and 5′-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC50 values of 0.4 μM, 1.1 μM, and <0.2 μM, respectively, as well as cell-associated virus with EC50 values of 12.6, 6.4, and 2.3 μM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either β-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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12 pages, 6564 KiB  
Article
Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors
by Pei-Tzu Huang, Sirle Saul, Shirit Einav and Christopher R. M. Asquith
Molecules 2021, 26(23), 7338; https://doi.org/10.3390/molecules26237338 - 3 Dec 2021
Cited by 4 | Viewed by 2165
Abstract
Emerging viral infections, including those caused by dengue virus (DENV) and Venezuelan Equine Encephalitis virus (VEEV), pose a significant global health challenge. Here, we report the preparation and screening of a series of 4-anilinoquinoline libraries targeting DENV and VEEV. This effort generated a [...] Read more.
Emerging viral infections, including those caused by dengue virus (DENV) and Venezuelan Equine Encephalitis virus (VEEV), pose a significant global health challenge. Here, we report the preparation and screening of a series of 4-anilinoquinoline libraries targeting DENV and VEEV. This effort generated a series of lead compounds, each occupying a distinct chemical space, including 3-((6-bromoquinolin-4-yl)amino)phenol (12), 6-bromo-N-(5-fluoro-1H-indazol-6-yl)quinolin-4-amine (50) and 6-((6-bromoquinolin-4-yl)amino)isoindolin-1-one (52), with EC50 values of 0.63–0.69 µM for DENV infection. These compound libraries demonstrated very limited toxicity with CC50 values greater than 10 µM in almost all cases. Additionally, the lead compounds were screened for activity against VEEV and demonstrated activity in the low single-digit micromolar range, with 50 and 52 demonstrating EC50s of 2.3 µM and 3.6 µM, respectively. The promising results presented here highlight the potential to further refine this series in order to develop a clinical compound against DENV, VEEV, and potentially other emerging viral threats. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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29 pages, 13005 KiB  
Article
Diterpenes/Diterpenoids and Their Derivatives as Potential Bioactive Leads against Dengue Virus: A Computational and Network Pharmacology Study
by Rasel Ahmed Khan, Rajib Hossain, Abolghasem Siyadatpanah, Khattab Al-Khafaji, Abul Bashar Ripon Khalipha, Dipta Dey, Umma Hafsa Asha, Partha Biswas, Abu Saim Mohammad Saikat, Hadi Ahmadi Chenari, Polrat Wilairatana and Muhammad Torequl Islam
Molecules 2021, 26(22), 6821; https://doi.org/10.3390/molecules26226821 - 11 Nov 2021
Cited by 22 | Viewed by 4449
Abstract
Dengue fever is a dangerous infectious endemic disease that affects over 100 nations worldwide, from Africa to the Western Pacific, and is caused by the dengue virus, which is transmitted to humans by an insect bite of Aedes aegypti. Millions of citizens have [...] Read more.
Dengue fever is a dangerous infectious endemic disease that affects over 100 nations worldwide, from Africa to the Western Pacific, and is caused by the dengue virus, which is transmitted to humans by an insect bite of Aedes aegypti. Millions of citizens have died as a result of dengue fever and dengue hemorrhagic fever across the globe. Envelope (E), serine protease (NS3), RNA-directed RNA polymerase (NS5), and non-structural protein 1 (NS1) are mostly required for cell proliferation and survival. Some of the diterpenoids and their derivatives produced by nature possess anti-dengue viral properties. The goal of the computational study was to scrutinize the effectiveness of diterpenoids and their derivatives against dengue viral proteins through in silico study. Methods: molecular docking was performed to analyze the binding affinity of compounds against four viral proteins: the envelope (E) protein, the NS1 protein, the NS3 protein, and the NS5 protein. Results: among the selected drug candidates, triptolide, stevioside, alepterolic acid, sphaeropsidin A, methyl dodovisate A, andrographolide, caesalacetal, and pyrimethamine have demonstrated moderate to good binding affinities (−8.0 to −9.4 kcal/mol) toward the selected proteins: E protein, NS3, NS5, and NS1 whereas pyrimethamine exerts −7.5, −6.3, −7.8, and −6.6 kcal/mol with viral proteins, respectively. Interestingly, the binding affinities of these lead compounds were better than those of an FDA-approved anti-viral medication (pyrimethamine), which is underused in dengue fever. Conclusion: we can conclude that diterpenoids can be considered as a possible anti-dengue medication option. However, in vivo investigation is recommended to back up the conclusions of this study. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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21 pages, 2305 KiB  
Article
In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine
by Vanessa Loaiza-Cano, Laura Milena Monsalve-Escudero, Manuel Pastrana Restrepo, Diana Carolina Quintero-Gil, Sergio Andres Pulido Muñoz, Elkin Galeano, Wildeman Zapata and Marlen Martinez-Gutierrez
Molecules 2021, 26(11), 3430; https://doi.org/10.3390/molecules26113430 - 5 Jun 2021
Cited by 4 | Viewed by 2850
Abstract
Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived [...] Read more.
Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina®, and the molecular dynamic with Gromacs®. Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and β2 adrenoreceptor. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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20 pages, 4030 KiB  
Article
In Vitro Inhibitory Analysis of Rationally Designed siRNAs against MERS-CoV Replication in Huh7 Cells
by Sherif Aly El-Kafrawy, Sayed Sartaj Sohrab, Zeenat Mirza, Ahmed M. Hassan, Fatima Alsaqaf and Esam Ibraheem Azhar
Molecules 2021, 26(9), 2610; https://doi.org/10.3390/molecules26092610 - 29 Apr 2021
Cited by 8 | Viewed by 1779
Abstract
MERS-CoV was identified for the first time in Jeddah, Saudi Arabia in 2012 in a hospitalized patient. This virus subsequently spread to 27 countries with a total of 939 deaths and 2586 confirmed cases and now has become a serious concern globally. Camels [...] Read more.
MERS-CoV was identified for the first time in Jeddah, Saudi Arabia in 2012 in a hospitalized patient. This virus subsequently spread to 27 countries with a total of 939 deaths and 2586 confirmed cases and now has become a serious concern globally. Camels are well known for the transmission of the virus to the human population. In this report, we have discussed the prediction, designing, and evaluation of potential siRNA targeting the ORF1ab gene for the inhibition of MERS-CoV replication. The online software, siDirect 2.0 was used to predict and design the siRNAs, their secondary structure and their target accessibility. ORF1ab gene folding was performed by RNAxs and RNAfold software. A total of twenty-one siRNAs were selected from 462 siRNAs according to their scoring and specificity. siRNAs were evaluated in vitro for their cytotoxicity and antiviral efficacy in Huh7 cell line. No significant cytotoxicity was observed for all siRNAs in Huh7 cells. The in vitro study showed the inhibition of viral replication by three siRNAs. The data generated in this study provide preliminary and encouraging information to evaluate the siRNAs separately as well as in combination against MERS-CoV replication in other cell lines. The prediction of siRNAs using online software resulted in the filtration and selection of potential siRNAs with high accuracy and strength. This computational approach resulted in three effective siRNAs that can be taken further to in vivo animal studies and can be used to develop safe and effective antiviral therapies for other prevalent disease-causing viruses. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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11 pages, 898 KiB  
Article
Synergistic Effect by Combining a gp120-Binding Protein and a gp41-Binding Antibody to Inactivate HIV-1 Virions and Inhibit HIV-1 Infection
by Xinling Wang, Miao Cao, Yanling Wu, Wei Xu, Qian Wang, Tianlei Ying, Lu Lu and Shibo Jiang
Molecules 2021, 26(7), 1964; https://doi.org/10.3390/molecules26071964 - 31 Mar 2021
Cited by 4 | Viewed by 2450
Abstract
Acquired immune deficiency syndrome (AIDS) has prevailed over the last 30 years. Although highly active antiretroviral therapy (HAART) has decreased mortality and efficiently controlled the progression of disease, no vaccine or curative drugs have been approved until now. A viral inactivator is expected [...] Read more.
Acquired immune deficiency syndrome (AIDS) has prevailed over the last 30 years. Although highly active antiretroviral therapy (HAART) has decreased mortality and efficiently controlled the progression of disease, no vaccine or curative drugs have been approved until now. A viral inactivator is expected to inactivate cell-free virions in the absence of target cells. Previously, we identified a gp120-binding protein, mD1.22, which can inactivate laboratory-adapted HIV-1. In this study, we have found that the gp41 N-terminal heptad repeat (NHR)-binding antibody D5 single-chain variable fragment (scFv) alone cannot inactivate HIV-1 at the high concentration tested. However, D5 scFv in the combination could enhance inactivation activity of mD1.22 against divergent HIV-1 strains, including HIV-1 laboratory-adapted strains, primary HIV-1 isolates, T20- and AZT-resistant strains, and LRA-reactivated virions. Combining mD1.22 and D5 scFv exhibited synergistic effect on inhibition of infection by divergent HIV-1 strains. These results suggest good potential to develop the strategy of combining a gp120-binding protein and a gp41-binding antibody for the treatment of HIV-1 infection. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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13 pages, 1793 KiB  
Article
Small Interfering RNAs Are Highly Effective Inhibitors of Crimean-Congo Hemorrhagic Fever Virus Replication In Vitro
by Fanni Földes, Mónika Madai, Henrietta Papp, Gábor Kemenesi, Brigitta Zana, Lili Geiger, Katalin Gombos, Balázs Somogyi, Ildikó Bock-Marquette and Ferenc Jakab
Molecules 2020, 25(23), 5771; https://doi.org/10.3390/molecules25235771 - 7 Dec 2020
Cited by 4 | Viewed by 2284
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is one of the prioritized diseases of the World Health Organization, considering its potential to create a public health emergency and, more importantly, the absence of efficacious drugs and/or vaccines for treatment. The highly pathogenic characteristic of CCHFV [...] Read more.
Crimean-Congo hemorrhagic fever virus (CCHFV) is one of the prioritized diseases of the World Health Organization, considering its potential to create a public health emergency and, more importantly, the absence of efficacious drugs and/or vaccines for treatment. The highly pathogenic characteristic of CCHFV restricts research to BSL-4 laboratories, which complicates effective research and developmental strategies. In consideration of antiviral therapies, RNA interference can be used to suppress viral replication by targeting viral genes. RNA interference uses small interfering RNAs (siRNAs) to silence genes. The aim of our study was to design and test siRNAs in vitro that inhibit CCHFV replication and can serve as a basis for further antiviral therapies. A549 cells were infected with CCHFV after transfection with the siRNAs. Following 72 h, nucleic acid from the supernatant was extracted for RT Droplet Digital PCR analysis. Among the investigated siRNAs we identified effective candidates against all three segments of the CCHF genome. Consequently, blocking any segment of CCHFV leads to changes in the virus copy number that indicates an antiviral effect of the siRNAs. In summary, we demonstrated the ability of specific siRNAs to inhibit CCHFV replication in vitro. This promising result can be integrated into future anti-CCHFV therapy developments. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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Review

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16 pages, 511 KiB  
Review
Progression of Antiviral Agents Targeting Viral Polymerases
by Siqi Peng, Huizhen Wang, Zhengtao Wang and Qingzhong Wang
Molecules 2022, 27(21), 7370; https://doi.org/10.3390/molecules27217370 - 29 Oct 2022
Cited by 8 | Viewed by 2839
Abstract
Viral DNA and RNA polymerases are two kinds of very important enzymes that synthesize the genetic materials of the virus itself, and they have become extremely favorable targets for the development of antiviral drugs because of their relatively conserved characteristics. There are many [...] Read more.
Viral DNA and RNA polymerases are two kinds of very important enzymes that synthesize the genetic materials of the virus itself, and they have become extremely favorable targets for the development of antiviral drugs because of their relatively conserved characteristics. There are many similarities in the structure and function of different viral polymerases, so inhibitors designed for a certain viral polymerase have acted as effective universal inhibitors on other types of viruses. The present review describes the development of classical antiviral drugs targeting polymerases, summarizes a variety of viral polymerase inhibitors from the perspective of chemically synthesized drugs and natural product drugs, describes novel approaches, and proposes promising development strategies for antiviral drugs. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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21 pages, 3101 KiB  
Review
RETRACTED: Artemisia Extracts and Artemisinin-Based Antimalarials for COVID-19 Management: Could These Be Effective Antivirals for COVID-19 Treatment?
by Pawan K. Agrawal, Chandan Agrawal and Gerald Blunden
Molecules 2022, 27(12), 3828; https://doi.org/10.3390/molecules27123828 - 14 Jun 2022
Cited by 17 | Viewed by 10570 | Retraction
Abstract
As the world desperately searches for ways to treat the coronavirus disease 2019 (COVID-19) pandemic, a growing number of people are turning to herbal remedies. The Artemisia species, such as A. annua and A. afra, in particular, exhibit positive effects against severe [...] Read more.
As the world desperately searches for ways to treat the coronavirus disease 2019 (COVID-19) pandemic, a growing number of people are turning to herbal remedies. The Artemisia species, such as A. annua and A. afra, in particular, exhibit positive effects against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and COVID-19 related symptoms. A. annua is a source of artemisinin, which is active against malaria, and also exhibits potential for other diseases. This has increased interest in artemisinin’s potential for drug repurposing. Artemisinin-based combination therapies, so-called ACTs, have already been recognized as first-line treatments against malaria. Artemisia extract, as well as ACTs, have demonstrated inhibition of SARS-CoV-2. Artemisinin and its derivatives have also shown anti-inflammatory effects, including inhibition of interleukin-6 (IL-6) that plays a key role in the development of severe COVID-19. There is now sufficient evidence in the literature to suggest the effectiveness of Artemisia, its constituents and/or artemisinin derivatives, to fight against the SARS-CoV-2 infection by inhibiting its invasion, and replication, as well as reducing oxidative stress and inflammation, and mitigating lung damage. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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19 pages, 3262 KiB  
Review
Can the SARS-CoV-2 Omicron Variant Confer Natural Immunity against COVID-19?
by Abdul Hawil Abas, Siti Marfuah, Rinaldi Idroes, Diah Kusumawaty, Fatimawali, Moon Nyeo Park, Abolghasem Siyadatpanah, Fahad A. Alhumaydhi, Shafi Mahmud, Trina Ekawati Tallei, Talha Bin Emran and Bonglee Kim
Molecules 2022, 27(7), 2221; https://doi.org/10.3390/molecules27072221 - 29 Mar 2022
Cited by 15 | Viewed by 5547
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, with no signs of abatement in sight. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of this pandemic and has claimed over 5 million lives, is still mutating, resulting [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, with no signs of abatement in sight. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of this pandemic and has claimed over 5 million lives, is still mutating, resulting in numerous variants. One of the newest variants is Omicron, which shows an increase in its transmissibility, but also reportedly reduces hospitalization rates and shows milder symptoms, such as in those who have been vaccinated. As a result, many believe that Omicron provides a natural vaccination, which is the first step toward ending the COVID-19 pandemic. Based on published research and scientific evidence, we review and discuss how the end of this pandemic is predicted to occur as a result of Omicron variants being surpassed in the community. In light of the findings of our research, we believe that it is most likely true that the Omicron variant is a natural way of vaccinating the masses and slowing the spread of this deadly pandemic. While the mutation that causes the Omicron variant is encouraging, subsequent mutations do not guarantee that the disease it causes will be less severe. As the virus continues to evolve, humans must constantly adapt by increasing their immunity through vaccination. Full article
(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)
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