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1
Hakem, Asma, Lowiese Desmarets, Ramla Sahli, Rawen Ben Malek, Charline Camuzet, Nathan François, Gabriel Lefèvre et al. "Luteolin Isolated from Juncus acutus L., a Potential Remedy for Human Coronavirus 229E". Molecules 28, n.º 11 (23 de mayo de 2023): 4263. http://dx.doi.org/10.3390/molecules28114263.
Resumen
The COVID-19 pandemic, caused by SARS-CoV-2, addressed the lack of specific antiviral drugs against coronaviruses. In this study, bioguided fractionation performed on both ethyl acetate and aqueous sub-extracts of Juncus acutus stems led to identifying luteolin as a highly active antiviral molecule against human coronavirus HCoV-229E. The apolar sub-extract (CH2Cl2) containing phenanthrene derivatives did not show antiviral activity against this coronavirus. Infection tests on Huh-7 cells, expressing or not the cellular protease TMPRSS2, using luciferase reporter virus HCoV-229E-Luc showed that luteolin exhibited a dose-dependent inhibition of infection. Respective IC50 values of 1.77 µM and 1.95 µM were determined. Under its glycosylated form (luteolin-7-O-glucoside), luteolin was inactive against HCoV-229E. Time of addition assay showed that utmost anti-HCoV-229E activity of luteolin was achieved when added at the post-inoculation step, indicating that luteolin acts as an inhibitor of the replication step of HCoV-229E. Unfortunately, no obvious antiviral activity for luteolin was found against SARS-CoV-2 and MERS-CoV in this study. In conclusion, luteolin isolated from Juncus acutus is a new inhibitor of alphacoronavirus HCoV-229E.
2
Parang, Keykavous, Naglaa Salem El-Sayed, Assad J. Kazeminy y Rakesh K. Tiwari. "Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs against Human Coronavirus 229E (HCoV-229E)". Molecules 25, n.º 10 (17 de mayo de 2020): 2343. http://dx.doi.org/10.3390/molecules25102343.
Resumen
Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5′-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5′-O-fatty acyl conjugates of NRTIs, 5′-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.
3
Chang, Fang-Rong, Chiao-Ting Yen, Mohamed EI-Shazly, Wen-Hsun Lin, Ming-Hong Yen, Kuei-Hsiang Lin y Yang-Chang Wu. "Anti-Human Coronavirus (anti-HCoV) Triterpenoids from the Leaves of Euphorbia Neriifolia". Natural Product Communications 7, n.º 11 (noviembre de 2012): 1934578X1200701. http://dx.doi.org/10.1177/1934578x1200701103.
Resumen
Euphorbia neriifolia L. is a spiny herb native to Southeast Asia and currently cultivated in southern Taiwan. From the ethanolic extract of E. neriifolia leaves, 23 compounds were isolated, including 22 triterpenoids and one flavonoid glycoside. The anti-human coronavirus (HCoV) activity of the separated triterpenoids was studied revealing the structure-activity relationship (SAR) of these isolates. 3β-Friedelanol exhibited more potent anti-viral activity than the positive control, actinomycin D, which implies the importance of the friedelane skeleton as a potential scaffold for developing new anti-HCoV-229E drugs.
4
Kwon, Eun-Bin, Buyun Kim, Young Soo Kim y Jang-Gi Choi. "Anastrozole Protects against Human Coronavirus Infection by Ameliorating the Reactive Oxygen Species–Mediated Inflammatory Response". Antioxidants 13, n.º 1 (17 de enero de 2024): 116. http://dx.doi.org/10.3390/antiox13010116.
Resumen
The common human coronavirus (HCoV) exhibits mild disease with upper respiratory infection and common cold symptoms. HCoV-OC43, one of the HCoVs, can be used to screen drug candidates against SARS-CoV-2. We determined the antiviral effects of FDA/EMA-approved drug anastrozole (AZ) on two human coronaviruses, HCoV-OC43 and HCoV-229E, using MRC-5 cells in vitro. The AZ exhibited antiviral effects against HCoV-OC43 and HCoV-229E infection. Subsequent studies focused on HCoV-OC43, which is related to the SARS-CoV-2 family. AZ exhibited anti-viral effects and reduced the secretion of inflammatory cytokines, TNF-α, IL-6, and IL-1β. It also inhibited NF-κB translocation to effectively suppress the inflammatory response. AZ reduced intracellular calcium and reactive oxygen species (ROS) levels, including mitochondrial ROS and Ca2+, induced by the virus. AZ inhibited the expression of NLRP3 inflammasome components and cleaved IL-1β, suggesting that it blocks NLRP3 inflammasome activation in HCoV-OC43-infected cells. Moreover, AZ enhanced cell viability and reduced the expression of cleaved gasdermin D (GSDMD), a marker of pyroptosis. Overall, we demonstrated that AZ exhibits antiviral activity against HCoV-OC43 and HCoV-229E. We specifically focused on its efficacy against HCoV-OC43 and showed its potential to reduce inflammation, inhibit NLRP3 inflammasome activation, mitigate mitochondrial dysfunction, and suppress pyroptosis in infected cells.
5
Al Mosawi, AJ. "Remdesivir Research Progress: An Overview of the Emerging Evidence". Journal of Biomedical Research & Environmental Sciences 1, n.º 6 (14 de octubre de 2020): 216–18. http://dx.doi.org/10.37871/jbres1146.
Resumen
There has been an increasing interest in remdesivir research within the scientific medical community because of the emerging evidence suggesting its beneficial role in patients with COVID‑19. Remdesivir which can be given intravenously and not orally has an anti-viral against several RNA viruses. Remdesivir has an in vitro antiviral activity against filoviruses, arenaviruses, and coronaviruses including circulating human coronaviruses HCoV-OC43, HCoV-229E, SARS, and MERS zoonotic coronaviruses.
6
Buchowicz, Włodzimierz y Mariola Koszytkowska-Stawińska. "How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses?" Organics 5, n.º 2 (8 de mayo de 2024): 71–110. http://dx.doi.org/10.3390/org5020006.
Resumen
Nucleoside analogs (NAs) have been extensively examined as plausible antiviral agents in recent years, in particular since the outbreak of the global pandemic of COVID-19 in 2019. In this review, the structures and antiviral properties of over 450 NAs are collected according to the type of virus, namely SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. The activity of the NAs against HCoV-related enzymes is also presented. Selected studies dealing with the mode of action of the NAs are discussed in detail. The repurposing of known NAs appears to be the most extensively investigated scientific approach towards efficacious anti-HCoV agents. The recently reported de novo-designed NAs seem to open up additional approaches to new drug candidates.
7
Chen, Lili, Chunshan Gui, Xiaomin Luo, Qingang Yang, Stephan Günther, Elke Scandella, Christian Drosten et al. "Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro". Journal of Virology 79, n.º 11 (1 de junio de 2005): 7095–103. http://dx.doi.org/10.1128/jvi.79.11.7095-7103.2005.
Resumen
ABSTRACT The 3C-like proteinase (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CLpro. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CLpro of SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC50) values of 5 μM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC50 values ranging from 19 to 34 μM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.
8
Pasquereau, Sébastien, Zeina Nehme, Sandy Haidar Ahmad, Fadoua Daouad, Jeanne Van Assche, Clémentine Wallet, Christian Schwartz, Olivier Rohr, Stéphanie Morot-Bizot y Georges Herbein. "Resveratrol Inhibits HCoV-229E and SARS-CoV-2 Coronavirus Replication In Vitro". Viruses 13, n.º 2 (23 de febrero de 2021): 354. http://dx.doi.org/10.3390/v13020354.
Resumen
A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drug repurposing embodies a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested seven compounds for their ability to reduce replication of human coronavirus (HCoV)-229E, another member of the coronavirus family. Among these seven drugs tested, four of them, namely rapamycin, disulfiram, loperamide and valproic acid, were highly cytotoxic and did not warrant further testing. In contrast, we observed a reduction of the viral titer by 80% with resveratrol (50% effective concentration (EC50) = 4.6 µM) and lopinavir/ritonavir (EC50 = 8.8 µM) and by 60% with chloroquine (EC50 = 5 µM) with very limited cytotoxicity. Among these three drugs, resveratrol was less cytotoxic (cytotoxic concentration 50 (CC50) = 210 µM) than lopinavir/ritonavir (CC50 = 102 µM) and chloroquine (CC50 = 67 µM). Thus, among the seven drugs tested against HCoV-229E, resveratrol demonstrated the optimal antiviral response with low cytotoxicity with a selectivity index (SI) of 45.65. Similarly, among the three drugs with an anti-HCoV-229E activity, namely lopinavir/ritonavir, chloroquine and resveratrol, only the latter showed a reduction of the viral titer on SARS-CoV-2 with reduced cytotoxicity. This opens the door to further evaluation to fight Covid-19.
9
Lan, Qiaoshuai, Chao Wang, Jie Zhou, Lijue Wang, Fanke Jiao, Yanbo Zhang, Yanxing Cai, Lu Lu, Shuai Xia y Shibo Jiang. "25-Hydroxycholesterol-Conjugated EK1 Peptide with Potent and Broad-Spectrum Inhibitory Activity against SARS-CoV-2, Its Variants of Concern, and Other Human Coronaviruses". International Journal of Molecular Sciences 22, n.º 21 (1 de noviembre de 2021): 11869. http://dx.doi.org/10.3390/ijms222111869.
Resumen
The COVID-19 pandemic caused by SARS-CoV-2 infection poses a serious threat to global public health and the economy. The enzymatic product of cholesterol 25-hydroxylase (CH25H), 25-Hydroxycholesterol (25-HC), was reported to have potent anti-SARS-CoV-2 activity. Here, we found that the combination of 25-HC with EK1 peptide, a pan-coronavirus (CoV) fusion inhibitor, showed a synergistic antiviral activity. We then used the method of 25-HC modification to design and synthesize a series of 25-HC-modified peptides and found that a 25-HC-modified EK1 peptide (EK1P4HC) was highly effective against infections caused by SARS-CoV-2, its variants of concern (VOCs), and other human CoVs, such as HCoV-OC43 and HCoV-229E. EK1P4HC could protect newborn mice from lethal HCoV-OC43 infection, suggesting that conjugation of 25-HC with a peptide-based viral inhibitor was a feasible and universal strategy to improve its antiviral activity.
10
Song, Yabin, Yongqiang Deng, Huiqiang Wang, Zhuchun Bei, Hongjing Gu, Hui Zhao, Hong Wang et al. "Naphthoquine: A Potent Broad-Spectrum Anti-Coronavirus Drug In Vitro". Molecules 27, n.º 3 (21 de enero de 2022): 712. http://dx.doi.org/10.3390/molecules27030712.
Resumen
COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC50 = 2.05 ± 1.44 μM, 5.83 ± 0.74 μM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection.
11
Liu, Weiyong, Min Zhang, Chengxiu Hu, Huijuan Song, Yi Mei, Yingle Liu y Qi Zhang. "Remdesivir Derivative VV116 Is a Potential Broad-Spectrum Inhibitor of Both Human and Animal Coronaviruses". Viruses 15, n.º 12 (23 de noviembre de 2023): 2295. http://dx.doi.org/10.3390/v15122295.
Resumen
Coronaviruses represent a significant threat to both human and animal health, encompassing a range of pathogenic strains responsible for illnesses, from the common cold to more severe diseases. VV116 is a deuterated derivative of Remdesivir with oral bioavailability that was found to potently inhibit SARS-CoV-2. In this work, we investigated the broad-spectrum antiviral activity of VV116 against a variety of human and animal coronaviruses. We examined the inhibitory effects of VV116 on the replication of the human coronaviruses HCoV-NL63, HCoV-229E, and HCoV-OC43, as well as the animal coronaviruses MHV, FIPV, FECV, and CCoV. The findings reveal that VV116 effectively inhibits viral replication across these strains without exhibiting cytotoxicity, indicating its potential for safe therapeutic use. Based on the results of a time-of-addition assay and an rNTP competitive inhibition assay, it is speculated that the inhibitory mechanism of VV116 against HCoV-NL63 is consistent with its inhibition of SARS-CoV-2. Our work presents VV116 as a promising candidate for broad-spectrum anti-coronavirus therapy, with implications for both human and animal health, and supports the expansion of its therapeutic applications as backed by detailed experimental data.
12
Tusell, Sonia M., Stephanie A. Schittone y Kathryn V. Holmes. "Mutational Analysis of Aminopeptidase N, a Receptor for Several Group 1 Coronaviruses, Identifies Key Determinants of Viral Host Range". Journal of Virology 81, n.º 3 (8 de noviembre de 2006): 1261–73. http://dx.doi.org/10.1128/jvi.01510-06.
Resumen
ABSTRACT Feline coronavirus (FCoV), porcine transmissible gastroenteritis coronavirus (TGEV), canine coronavirus (CCoV), and human coronavirus HCoV-229E, which belong to the group 1 coronavirus, use aminopeptidase N (APN) of their natural host and feline APN (fAPN) as receptors. Using mouse-feline APN chimeras, we identified three small, discontinuous regions, amino acids (aa) 288 to 290, aa 732 to 746 (called R1), and aa 764 to 788 (called R2) in fAPN that determined the host ranges of these coronaviruses. Blockade of infection with anti-fAPN monoclonal antibody RG4 suggested that these three regions lie close together on the fAPN surface. Different residues in fAPN were required for infection with each coronavirus. HCoV-229E infection was blocked by an N-glycosylation sequon present between aa 288 to 290 in murine APN. TGEV required R1 of fAPN, while FCoV and CCoV required both R1 and R2 for entry. N740 and T742 in fAPN and the homologous R741 in human APN (hAPN) were key determinants of host range for FCoV, TGEV, and CCoV. Residue N740 in fAPN was essential only for CCoV receptor activity. A conservative T742V substitution or a T742R substitution in fAPN destroyed receptor activity for the pig, dog, and cat coronaviruses, while a T742S substitution retained these receptor activities. Thus, the hydroxyl on T742 is required for the coronavirus receptor activity of fAPN. In hAPN an R741T substitution caused a gain of receptor activity for TGEV but not for FCoV or CCoV. Therefore, entry and host range of these group 1 coronaviruses depend on the ability of the viral spike glycoproteins to recognize small, species-specific amino acid differences in the APN proteins of different species.
13
Calistri, Arianna, Anna Luganini, Barbara Mognetti, Elizabeth Elder, Giulia Sibille, Valeria Conciatori, Claudia Del Vecchio et al. "The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses". Microorganisms 9, n.º 8 (14 de agosto de 2021): 1731. http://dx.doi.org/10.3390/microorganisms9081731.
Resumen
Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.
14
Bege, Miklós, Alexandra Kiss, Ilona Bereczki, Jan Hodek, Lenke Polyák, Gábor Szemán-Nagy, Lieve Naesens, Jan Weber y Anikó Borbás. "Synthesis and Anticancer and Antiviral Activities of C-2′-Branched Arabinonucleosides". International Journal of Molecular Sciences 23, n.º 20 (19 de octubre de 2022): 12566. http://dx.doi.org/10.3390/ijms232012566.
Resumen
d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2’ position were prepared from the corresponding 3’,5’-O-silylene acetal-protected nucleoside 2’-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2’-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl β-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2’ substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2’-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.
15
Shahhamzehei, Nasim, Sara Abdelfatah y Thomas Efferth. "In Silico and In Vitro Identification of Pan-Coronaviral Main Protease Inhibitors from a Large Natural Product Library". Pharmaceuticals 15, n.º 3 (3 de marzo de 2022): 308. http://dx.doi.org/10.3390/ph15030308.
Resumen
The main protease (Mpro or 3CLpro) in coronaviruses represents a promising specific drug target as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that does not exist in human host proteases. In this study, we explored potential natural pan-coronavirus drugs using in vitro and in silico approaches and three coronavirus main proteases as treatment targets. The PyRx program was used to screen 39,442 natural-product-like compounds from the ZINC database and 121 preselected phytochemicals from medicinal plants with known antiviral activity. After assessment with Lipinski’s rule of five, molecular docking was performed for the top 33 compounds of both libraries. Enzymatic assays were applied for the top candidates from both in silico approaches to test their ability to inhibit SARS-CoV-2 Mpro. The four compounds (hypericin, rosmarinic acid, isorhamnetin, and luteolin) that most efficiently inhibited SARS-CoV-2 Mpro in vitro were further tested for their efficacy in inhibiting Mpro of SARS-CoV-1 and MERS-CoV. Microscale thermophoresis was performed to determine dissociation constant (Kd) values to validate the binding of these active compounds to recombinant Mpro proteins of SARS-CoV-2, SARS-CoV-1, and MERS-CoV. The cytotoxicity of hypericin, rosmarinic acid, isorhamnetin, and luteolin was assessed in human diploid MRC-5 lung fibroblasts using the resazurin cell viability assay to determine their therapeutic indices. Sequence alignment of Mpro of SARS-CoV-2 demonstrated 96.08%, 50.83%, 49.17%, 48.51%, 44.04%, and 41.06% similarity to Mpro of other human-pathogenic coronaviruses (SARS-CoV-1, MERS-CoV, HCoV-NL63, HCoV-OC43, HCoV-HKU1, and HCoV-229E, respectively). Molecular docking showed that 12 out of 121 compounds were bound to SARS-CoV-2 Mpro at the same binding site as the control inhibitor, GC376. Enzyme inhibition assays revealed that hypericin, rosmarinic acid, isorhamnetin, and luteolin inhibited Mpro of SARS-CoV-2, while hypericin and isorhamnetin inhibited Mpro of SARS-CoV-1; hypericin showed inhibitory effects toward Mpro of MERS-CoV. Microscale thermophoresis confirmed the binding of these compounds to Mpro with high affinity. Resazurin assays showed that rosmarinic acid and luteolin were not cytotoxic toward MRC-5 cells, whereas hypericin and isorhamnetin were slightly cytotoxic. We demonstrated that hypericin represents a potential novel pan-anti-coronaviral agent by binding to and inhibiting Mpro of several human-pathogenic coronaviruses. Moreover, isorhamnetin showed inhibitory effects toward SARS-CoV-2 and SARS-CoV-1 Mpro, indicating that this compound may have some pan-coronaviral potential. Luteolin had inhibitory effects against SARS-CoV-2 Mpro.
16
Ambrosino, Annalisa, Annalisa Chianese, Carla Zannella, Simona Piccolella, Severina Pacifico, Rosa Giugliano, Gianluigi Franci et al. "Galdieria sulphuraria: An Extremophilic Alga as a Source of Antiviral Bioactive Compounds". Marine Drugs 21, n.º 7 (28 de junio de 2023): 383. http://dx.doi.org/10.3390/md21070383.
Resumen
In the last decades, the interest in bioactive compounds derived from natural sources including bacteria, fungi, plants, and algae has significantly increased. It is well-known that aquatic or terrestrial organisms can produce, in special conditions, secondary metabolites with a wide range of biological properties, such as anticancer, antioxidant, anti-inflammatory, and antimicrobial activities. In this study, we focused on the extremophilic microalga Galdieria sulphuraria as a possible producer of bioactive compounds with antiviral activity. The algal culture was subjected to organic extraction with acetone. The cytotoxicity effect of the extract was evaluated by the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The antiviral activity was assessed through a plaque assay against herpesviruses and coronaviruses as enveloped viruses and poliovirus as a naked one. The monolayer was treated with different concentrations of extract, ranging from 1 µg/mL to 200 µg/mL, and infected with viruses. The algal extract displayed strong antiviral activity at non-toxic concentrations against all tested enveloped viruses, in particular in the virus pre-treatment against HSV-2 and HCoV-229E, with IC50 values of 1.7 µg/mL and IC90 of 1.8 µg/mL, respectively. However, no activity against the non-enveloped poliovirus has been detected. The inhibitory effect of the algal extract was confirmed by the quantitative RT-PCR of viral genes. Preliminary chemical profiling of the extract was performed using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS), revealing the enrichment in primary fatty acid amides (PFAA), such as oleamide, palmitamide, and pheophorbide A. These promising results pave the way for the further purification of the mixture to explore its potential role as an antiviral agent.
17
Obermann, Wiebke, Alexandra Friedrich, Ramakanth Madhugiri, Paul Klemm, Jan Philipp Mengel, Torsten Hain, Stephan Pleschka et al. "Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity". Viruses 14, n.º 3 (3 de marzo de 2022): 519. http://dx.doi.org/10.3390/v14030519.
Resumen
Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.
18
Al Ibrahim, Malak, Zachee Louis Evariste Akissi, Lowiese Desmarets, Gabriel Lefèvre, Jennifer Samaillie, Imelda Raczkiewicz, Sevser Sahpaz et al. "Discovery of Anti-Coronavirus Cinnamoyl Triterpenoids Isolated from Hippophae rhamnoides during a Screening of Halophytes from the North Sea and Channel Coasts in Northern France". International Journal of Molecular Sciences 24, n.º 23 (22 de noviembre de 2023): 16617. http://dx.doi.org/10.3390/ijms242316617.
Resumen
The limited availability of antiviral therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred the search for novel antiviral drugs. Here, we investigated the potential antiviral properties of plants adapted to high-salt environments collected in the north of France. Twenty-five crude methanolic extracts obtained from twenty-two plant species were evaluated for their cytotoxicity and antiviral effectiveness against coronaviruses HCoV-229E and SARS-CoV-2. Then, a bioguided fractionation approach was employed. The most active crude methanolic extracts were partitioned into three different sub-extracts. Notably, the dichloromethane sub-extract of the whole plant Hippophae rhamnoides L. demonstrated the highest antiviral activity against both viruses. Its chemical composition was evaluated by ultra-high performance liquid chromatography (UHPLC) coupled with mass spectrometry (MS) and then it was fractionated by centrifugal partition chromatography (CPC). Six cinnamoyl triterpenoid compounds were isolated from the three most active fractions by preparative high-performance liquid chromatography (HPLC) and identified by high resolution MS (HR-MS) and mono- and bi-dimensional nuclear magnetic resonance (NMR). Specifically, these compounds were identified as 2-O-trans-p-coumaroyl-maslinic acid, 3β-hydroxy-2α-trans-p-coumaryloxy-urs-12-en-28-oic acid, 3β-hydroxy-2α-cis-p-coumaryloxy-urs-12-en-28-oic acid, 3-O-trans-caffeoyl oleanolic acid, a mixture of 3-O-trans-caffeoyl oleanolic acid/3-O-cis-caffeoyl oleanolic acid (70/30), and 3-O-trans-p-coumaroyl oleanolic acid. Infection tests demonstrated a dose-dependent inhibition of these triterpenes against HCoV-229E and SARS-CoV-2. Notably, cinnamoyl oleanolic acids displayed activity against both SARS-CoV-2 and HCoV-229E. Our findings suggest that Hippophae rhamnoides could represent a source of potential antiviral agents against coronaviruses.
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Shishkova, Kalina, Antoniya Stoymirska, Radoslav Chayrov, Stoyan Shishkov, Hristina Sbirkova-Dimitrova, Rusi Rusew, Boris Shivachev y Ivanka Stankova. "Amantadine and Rimantadine Analogues—Single-Crystal Analysis and Anti-Coronaviral Activity". Crystals 13, n.º 9 (14 de septiembre de 2023): 1374. http://dx.doi.org/10.3390/cryst13091374.
Resumen
In this study, we utilized the human coronavirus 229E (HCoV-229E) for evaluating the in vitro efficacy of some analogues of the ion-channel inhibitors and Amantadine and Rimantadine. The application of these investigated compounds did not result in any detectable cytotoxic effects. Furthermore, we observed that the derivatives of both analogues did not affect the viability of MDBK cells. Amantadine and Rimantadine applied at a concentration of 50 μg/mL inhibited the replication by 47% and 36%, respectively. The derivatives of Amantadine displayed a slightly weaker inhibitory effect in comparison with its own inhibitory effect. The derivative 4R of Rimantadine exhibited the same antiviral effect as the Rimantadine control, inhibiting viral replication by 37%. However, the other two derivatives of Rimantadine demonstrated lower activities. The molecular structures of the newly synthesized compounds were investigated thoroughly using single-crystal X-ray analysis. Molecular docking studies were performed using Autodock Vina. Two of the studied compounds 2A and 4A showed a promising binding affinity (−8.3 and −8.0 kcal/mol) towards SARS-CoV-2 RNA-dependent polymerase RNA site and SARS-CoV-2 Nsp3 (207-379, MES site) respectively.
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Andreu, Sabina, Inés Ripa, Raquel Bello-Morales y José Antonio López-Guerrero. "Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro". Viruses 15, n.º 4 (15 de abril de 2023): 972. http://dx.doi.org/10.3390/v15040972.
Resumen
A limited number of effective therapies are currently available to treat human coronavirus SARS-CoV-2 and other human coronaviruses, which are responsible for nearly a third of global cases of the common cold. The possibility of new emerging coronaviruses demands powerful new antiviral strategies. Lactoferrin is a well-known protein that possesses anti-inflammatory and immunomodulatory activities, and it has previously shown antiviral activity against several viruses, including SARS-CoV-2. To increase this antiviral activity, here we present bovine liposomal lactoferrin. Liposomal encapsulation of the compound was proven to increase permeability, bioavailability, and time release. In the present work, we compare the antiviral activity of free and liposomal bovine lactoferrin against HCoV229E and SARS-CoV-2 in vitro and in human primary bronchial epithelial cells, and we demonstrated that the liposomal form exerts a more potent antiviral activity than its free form at non-cytotoxic doses.
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Piacentini, Sara, Anna Riccio, Silvia Santopolo, Silvia Pauciullo, Simone La Frazia, Antonio Rossi, Jean-Francois Rossignol y M. Gabriella Santoro. "The FDA-approved drug nitazoxanide is a potent inhibitor of human seasonal coronaviruses acting at postentry level: effect on the viral spike glycoprotein". Frontiers in Microbiology 14 (29 de agosto de 2023). http://dx.doi.org/10.3389/fmicb.2023.1206951.
Resumen
Coronaviridae is recognized as one of the most rapidly evolving virus family as a consequence of the high genomic nucleotide substitution rates and recombination. The family comprises a large number of enveloped, positive-sense single-stranded RNA viruses, causing an array of diseases of varying severity in animals and humans. To date, seven human coronaviruses (HCoV) have been identified, namely HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1, which are globally circulating in the human population (seasonal HCoV, sHCoV), and the highly pathogenic SARS-CoV, MERS-CoV and SARS-CoV-2. Seasonal HCoV are estimated to contribute to 15–30% of common cold cases in humans; although diseases are generally self-limiting, sHCoV can sometimes cause severe lower respiratory infections and life-threatening diseases in a subset of patients. No specific treatment is presently available for sHCoV infections. Herein we show that the anti-infective drug nitazoxanide has a potent antiviral activity against three human endemic coronaviruses, the Alpha-coronaviruses HCoV-229E and HCoV-NL63, and the Beta-coronavirus HCoV-OC43 in cell culture with IC50 ranging between 0.05 and 0.15 μg/mL and high selectivity indexes. We found that nitazoxanide does not affect HCoV adsorption, entry or uncoating, but acts at postentry level and interferes with the spike glycoprotein maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Altogether the results indicate that nitazoxanide, due to its broad-spectrum anti-coronavirus activity, may represent a readily available useful tool in the treatment of seasonal coronavirus infections.
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Cai, Yanxing, Wei Xu, Jiayi Tang, Najing Cao, Qiaoshuai Lan, Lu Lu y Shibo Jiang. "A bivalent protein targeting glycans and HR1 domain in spike protein potently inhibited infection of SARS-CoV-2 and other human coronaviruses". Cell & Bioscience 11, n.º 1 (8 de julio de 2021). http://dx.doi.org/10.1186/s13578-021-00638-w.
Resumen
Abstract Background Our previous studies have shown that combining the antiviral lectin GRFT and the pan-CoV fusion inhibitory peptide EK1 results in highly potent inhibitory activity against SARS-CoV-2 infection. In this study, we aimed to design and construct a bivalent protein consisting of GRFT and EK1 components and evaluate its inhibitory activity and mechanism of action against infection by SARS-CoV-2 and its mutants, as well as other human coronaviruses (HCoVs). Methods The bivalent proteins were expressed in E. coli and purified with Ni-NTA column. HIV backbone-based pseudovirus (PsV) infection and HCoV S-mediated cell–cell fusion assays were performed to test their inhibitory activity. ELISA and Native-PAGE were conducted to illustrate the mechanism of action of these bivalent proteins. Five-day-old newborn mice were intranasally administrated with a selected bivalent protein before or after HCoV-OC43 challenge, and its protective effect was monitored for 14 days. Results Among the three bivalent proteins purified, GL25E exhibited the most potent inhibitory activity against infection of SARS-CoV-2 PsVs expressing wild-type and mutated S protein. GL25E was significantly more effective than GRFT and EK1 alone in inhibiting HCoV S-mediated cell–cell fusion, as well as infection by SARS-CoV-2 and other HCoVs, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and HCoV-OC43. GL25E could inhibit authentic SASR-CoV-2, HCoV-OC43 and HCoV-229E infection in vitro and prevent newborn mice from authentic HCoV-OC43 infection in vivo. GL25E could bind to glycans in the S1 subunit and HR1 in the S2 subunit in S protein, showing a mechanism of action similar to that of GRFT and EK1 alone. Conclusions Since GL25E showed highly potent and broad-spectrum inhibitory activity against infection of SARS-CoV-2 and its mutants, as well as other HCoVs, it is a promising candidate for further development as a broad-spectrum anti-HCoV therapeutic and prophylactic to treat and prevent COVID-19 and other emerging HCoV diseases.
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Elango, Abinaya. "In-vitro Assessment of Antiviral Activity of the Herbo Mineral Capsule, Fema SakthiTM, against Human Coronavirus (HCoV) on VERO Cells". Journal of Communicable Diseases, 16 de marzo de 2022, 120–23. http://dx.doi.org/10.24321/0019.5138.202219.
Resumen
Introduction: With the spread of COVID-19 pandemic, healthcare workers and patients look for alternate medicines including Siddha, Ayurveda, Unani and other forms of traditional medicines as we still do not have promising antiviral drugs for COVID-19. Objective: To evaluate the in-vitro antiviral activity of Fema Sakthi™ (FS) by eliciting the inhibition of cytopathic effect of Human Coronavirus (HCoV) on African Green Monkey kidney cells (VERO cells). Materials and Method:The cytopathic effect (CPE) was performed on Vero cells with Human Coronavirus 229E, a type of Coronavirus associated with respiratory infections. The Median Tissue Culture Infectious Dose (TCID50) was evaluated using Reed-Muench method. 100 TCID50 of HCoV 229E viral suspensions were added to VERO cell culture to induce the cytopathic effect. Uninfected and untreated cells were used as control and five concentrations (62.5, 125, 250, 500 & 1000 μg/mL) of Fema Sakthi™ (FS) were used to study the anti-viral activity. After incubation for 72 hours, the cell viability was observed under the inverted microscope after staining with 0.1% crystal violet. Results: Fema Sakthi™ (FS) was found to exhibit inhibition of cytopathic effect at lower concentrations (62.5, 125 and 250 μg/mL) but at higher concentrations (500 and 1000 μg/mL), the formulation itself was cytotoxic to the cells. Conclusion: This preliminary study showed that FS has antiviral activity at lower concentrations 62.5, 125 and 250 μg/mL on the VERO cells. However, further specific studies have to be carried out to confirm the anti-viral activity and clinical efficacy using other preclinical and clinical models of Human Coronavirus (HCoV) including COVID-19.
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Bai, Xiyuan, Ashley M. Buckle, Eszter K. Vladar, Edward N. Janoff, Reeti Khare, Diane Ordway, David Beckham et al. "Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19". Scientific Reports 12, n.º 1 (25 de marzo de 2022). http://dx.doi.org/10.1038/s41598-022-09133-9.
Resumen
AbstractThe cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin–TMPRSS2–AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2–AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19.
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Hegazy, Ghada E., Marwa M. Abu-Serie, Nadia A. Soliman, Mohamed Teleb y Yasser R. Abdel-Fattah. "Superior anti-pulmonary viral potential of Natrialba sp. M6-producing surfactin and C50 carotenoid pigment with unveiling its action modes". Virology Journal 20, n.º 1 (30 de octubre de 2023). http://dx.doi.org/10.1186/s12985-023-02215-8.
Resumen
Abstract Background Respiratory viruses, particularly adenoviruses (ADV), influenza A virus (e.g., H1N1), and coronaviruses (e.g., HCoV-229E and SARS-CoV-2) pose a global public health problem. Therefore, developing natural wide-spectrum antiviral compounds for disrupting the viral life cycle with antioxidant activity provides an efficient treatment approach. Herein, biosurfactant (Sur) and C50 carotenoid pigment (Pig) of haloalkaliphilic archaeon Natrialba sp. M6 which exhibited potent efficacy against hepatitis and anti-herpes simplex viruses, were investigated against pulmonary viruses. Methods The cytotoxicity of the extracted Sur and Pig was examined on susceptible cell lines for ADV, HIN1, HCoV-229E, and SARS-CoV-2. Their potential against the cytopathic activity of these viruses was detected with investigating the action modes (including, virucidal, anti-adsorption, and anti-replication), unveiling the main mechanisms, and using molecular docking analysis. Radical scavenging activity was determined and HPLC analysis for potent extract (Sur) was performed. Results All current investigations stated higher anti-pulmonary viruses of Sur than Pig via mainly virucidal and/or anti-replicative modes. Moreover, Sur had stronger ADV’s capsid protein binding, ADV’s DNA polymerase inhibition, suppressing hemagglutinin and neuraminidase of H1N1, and inhibiting chymotrypsin-like (3CL) protease of SARS-CoV-2, supporting with in-silico analysis, as well as radical scavenging activity than Pig. HPLC analysis of Sur confirmed the predominate presence of surfactin in it. Conclusion This study declared the promising efficacy of Sur as an efficient pharmacological treatment option for these pulmonary viruses and considered as guide for further in vivo research.
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Pasquereau, Sébastien, Mathilde Galais, Maxime Bellefroid, Irene Pachón Angona, Stéphanie Morot-Bizot, Lhassane Ismaili, Carine Van Lint y Georges Herbein. "Ferulic acid derivatives block coronaviruses HCoV-229E and SARS-CoV-2 replication in vitro". Scientific Reports 12, n.º 1 (24 de noviembre de 2022). http://dx.doi.org/10.1038/s41598-022-24682-9.
Resumen
AbstractA novel coronavirus, SARS-CoV-2, emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drugs with broad anti-coronavirus activity embody a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested ten small-molecules with chemical structures close to ferulic acid derivatives (FADs) (n = 8), caffeic acid derivatives (CAFDs) (n = 1) and carboxamide derivatives (CAMDs) (n = 1) for their ability to reduce HCoV-229E replication, another member of the coronavirus family. Among these ten drugs tested, five of them namely MBA112, MBA33, MBA27-1, OS4-1 and MBA108-1 were highly cytotoxic and did not warrant further testing. In contrast, we observed a moderate cytotoxicity for two of them, MBA152 and 5c. Three drugs, namely MBA140, LIJ2P40, and MBA28 showed lower cytotoxicity. These candidates were then tested for their antiviral propreties against HCoV-229E and SARS-CoV2 replication. We first observed encouraging results in HCoV-229E. We then measured a reduction of the viral SARS-CoV2 replication by 46% with MBA28 (EC50 > 200 µM), by 58% with MBA140 (EC50 = 176 µM), and by 82% with LIJ2P40 (EC50 = 66.5 µM). Overall, the FAD LIJ2P40 showed a reduction of the viral titer on SARS-CoV-2 up to two logs with moderate cytotoxicity which opens the door to further evaluation to fight Covid-19.
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Singh, Prachi, Ardra P, Hariprasad V.R., Babu U.V., Mohamed Rafiq y Raghavendra Pralhada Rao. "Screening for Potential Traditional Herbal Inhibitors Against 3-Chymotrypsin-Like Main Protease (3CLpro) from Four Different Coronaviruses-: An in-silico Approach". Coronaviruses 02 (16 de febrero de 2021). http://dx.doi.org/10.2174/2666796702666210216142508.
Resumen
Background: The recent outbreak of the COVID-19 pandemic has raised a global health concern due to the unavailability of any vaccines or drugs. The repurposing of traditional herbs with broad-spectrum anti-viral activity can be explored to control or prevent a pandemic. Objective: The 3-chymotrypsin-like main protease (3CLpro), also referred to as the “Achilles’ heel” of the coronaviruses (CoVs), is highly conserved among CoVs and is a potential drug target. 3CLpro is essential for the virus’s life cycle. The objective of the study was to screen and identify broad-spectrum natural phytoconstituents against the conserved active site and substrate-binding site of 3CLpro of HCoVs. Methods: Herein, we applied the computational strategy based on molecular docking to identify potential phytoconstituents for the non-covalent inhibition of the main protease 3CLpro from four different CoVs, namely, SARS-CoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Results: Our study shows that natural phytoconstituents in Triphala (a blend of Emblica Officinalis fruit, Terminalia bellerica fruit, and Terminalia chebula fruit), namely chebulagic acid, chebulinic acid, and elagic acid, exhibited the highest binding affinity and lowest dissociation constants (Ki), against the conserved 3CLpro main protease of SARSCoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Besides, phytoconstituents of other herbs like Withania somnifera, Glycyrrhiza glabra, Hyssopus officinalis, Camellia sinensis, Prunella vulgaris, and Ocimum sanctum also showed good binding affinity and lower Ki against the active site of 3CLpro. The top-ranking phytoconstituents’ binding interactions clearly showed a strong and stable interactions with amino acid residues in the catalytic dyad (CYS-HIS) and substrate-binding pocket of the 3CLpro main proteases. Conclusion: This study provides a valuable scaffold for repurposing traditional herbs with anti-CoV activity to combat SARS-CoV-2 and other HCoVs until the discovery of new therapies.
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Sharwani, Khalid, Ravi Sharma, Madhan Krishnan, Terry Jones, Martin Mayora-Neto, Diego Cantoni, Nigel A. Temperton et al. "Detection of serum cross-reactive antibodies and memory response to SARS-CoV-2 in pre-pandemic and post-COVID-19 convalescent samples". Journal of Infectious Diseases, 23 de junio de 2021. http://dx.doi.org/10.1093/infdis/jiab333.
Resumen
Abstract Background A notable feature of COVID-19 is that children are less susceptible to severe disease. Children are known to experience more infections with endemic human coronaviruses (HCoVs) compared to adults. Little is known whether HCoV infections lead to cross-reactive anti-SARS-CoV-2 antibodies. Methods We investigated the presence of cross-reactive anti-SARS-CoV-2 IgG antibodies (to spike(S)1, S1-receptor-binding receptor (S1-RBD) and nucleocapsid protein(NP)), by enzyme-linked immunosorbent assays, and neutralizing activity by a SARS-CoV-2 pseudotyped virus neutralisation assay, in pre-pandemic sera collected from children(n=50) and adults(n=45), and compared with serum samples from convalescent COVID-19 patients(n=16). Results A significant proportion of children (up to 40%) had detectable cross-reactive antibodies to SARS-CoV-2 S1, S1-RBD and NP antigens, and the anti-S1 and -S1-RBD antibody levels correlated with anti-HCoV-HKU1 and -OC43 S1 antibody titers in pre-pandemic samples(p<0.001). There were marked increases of anti-HCoV-HKU1 and -OC43 S1 (but not anti-NL63 and -229E S-RBD) antibody titres in serum samples from convalescent COVID-19 patients(p<0.001), indicating an activation of cross-reactive immunological memory to β-coronavirus spike. Conclusions We demonstrated cross-reactive anti-SARS-CoV-2 antibodies in pre-pandemic serum samples from children and young adults. Promoting this cross-reactive immunity and memory response derived from common HCoV may be an effective strategy against SARS-COV-2 and future novel coronaviruses.
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Shapira, Tirosh, Selvarani Vimalanathan, Celine Rens, Virginia Pichler, Sandra Peña-Díaz, Grace Jordana, William Rees et al. "Inhibition of glycogen synthase kinase-3-beta (GSK3β) blocks nucleocapsid phosphorylation and SARS-CoV-2 replication". Molecular Biomedicine 3, n.º 1 (12 de diciembre de 2022). http://dx.doi.org/10.1186/s43556-022-00111-1.
Resumen
AbstractGSK3β has been proposed to have an essential role in Coronaviridae infections. Screening of a targeted library of GSK3β inhibitors against both SARS-CoV-2 and HCoV-229E to identify broad-spectrum anti-Coronaviridae inhibitors resulted in the identification of a high proportion of active compounds with low toxicity to host cells. A selected lead compound, T-1686568, showed low micromolar, dose-dependent activity against SARS-CoV-2 and HCoV-229E. T-1686568 showed efficacy in viral-infected cultured cells and primary 2D organoids. T-1686568 also inhibited SARS-CoV-2 variants of concern Delta and Omicron. Importantly, while inhibition by T-1686568 resulted in the overall reduction of viral load and protein translation, GSK3β inhibition resulted in cellular accumulation of the nucleocapsid protein relative to the spike protein. Following identification of potential phosphorylation sites of Coronaviridae nucleocapsid, protein kinase substrate profiling assays combined with Western blotting analysis of nine host kinases showed that the SARS-CoV-2 nucleocapsid could be phosphorylated by GSK3β and PKCa. GSK3β phosphorylated SARS-CoV-2 nucleocapsid on the S180/S184, S190/S194 and T198 phospho-sites, following previous priming in the adjacent S188, T198 and S206, respectively. Such inhibition presents a compelling target for broad-spectrum anti-Coronaviridae compound development, and underlies the mechanism of action of GSK3β host-directed therapy against this class of obligate intracellular pathogens.
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Zhang, Yumin, Yuan Sun, Yuanchao Xie, Weijuan Shang, Zhen Wang, Hualiang Jiang, Jingshan Shen, Gengfu Xiao y Leike Zhang. "A viral RNA-dependent RNA polymerase inhibitor VV116 broadly inhibits human coronaviruses and has synergistic potency with 3CLpro inhibitor nirmatrelvir". Signal Transduction and Targeted Therapy 8, n.º 1 (22 de septiembre de 2023). http://dx.doi.org/10.1038/s41392-023-01587-1.
Resumen
AbstractDuring the ongoing pandemic, providing treatment consisting of effective, low-cost oral antiviral drugs at an early stage of SARS-CoV-2 infection has been a priority for controlling COVID-19. Although Paxlovid and molnupiravir have received emergency approval from the FDA, some side effect concerns have emerged, and the possible oral agents are still limited, resulting in optimized drug development becoming an urgent requirement. An oral remdesivir derivative, VV116, has been reported to have promising antiviral effects against SARS-CoV-2 and positive therapeutic outcomes in clinical trials. However, whether VV116 has broad-spectrum anti-coronavirus activity and potential synergy with other drugs is not clear. Here, we uncovered the broad-spectrum antiviral potency of VV116 against SARS-CoV-2 variants of concern (VOCs), HCoV-OC43, and HCoV-229E in various cell lines. In vitro drug combination screening targeted RdRp and proteinase, highlighting the synergistic effect of VV116 and nirmatrelvir on HCoV-OC43 and SARS-CoV-2. When co-administrated with ritonavir, the combination of VV116 and nirmatrelvir showed significantly enhanced antiviral potency with noninteracting pharmacokinetic properties in mice. Our findings will facilitate clinical treatment with VV116 or VV116+nirmatrelvir combination to fight coronavirus infection.
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Kirby, Emily N., Xavier B. Montin, Timothy P. Allen, Jaslan Densumite, Brooke N. Trowbridge y Michael R. Beard. "CRISPR activation as a platform to identify interferon stimulated genes with anti-viral function". Innate Immunity, 23 de enero de 2024. http://dx.doi.org/10.1177/17534259231225611.
Resumen
Interferon Stimulated Gene (ISG) expression plays a key role in the control of viral replication and development of a robust adaptive response. Understanding this dynamic relationship between the pathogen and host is critical to our understanding of viral life-cycles and development of potential novel anti-viral strategies. Traditionally, plasmid based exogenous prompter driven expression of ISGs has been used to investigate anti-viral ISG function, however there are deficiencies in this approach. To overcome this, we investigated the utility of CRISPR activation (CRISPRa), which allows for targeted transcriptional activation of a gene from its endogenous promoter. Using the CRISPRa-SAM system to induce targeted expression of a panel of anti-viral ISGs we showed robust induction of mRNA and protein expression. We then employed our CRISPRa-SAM ISG panel in several antiviral screen formats to test for the ability of ISGs to prevent viral induced cytopathic cell death (CPE) and replication of Dengue Virus (DENV), Zika Virus (ZIKV), West Nile Virus Kunjin (WNVKUN), Hepatitis A Virus (HAV) and Human Coronavirus 229E (HCoV-229E). Our CRISPRa approach confirmed the anti-viral activity of ISGs like IFI6, IFNβ and IFNλ2 that prevented viral induced CPE, which was supported by high-content immunofluorescence imaging analysis. This work highlights CRISPRa as a rapid, agile, and powerful methodology to identify and characterise ISGs and viral restriction factors.
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Yuan, Shuofeng, Xiaopan Gao, Kaiming Tang, Jian-Piao Cai, Menglong Hu, Peng Luo, Lei Wen et al. "Targeting papain-like protease for broad-spectrum coronavirus inhibition". Protein & Cell, 6 de abril de 2022. http://dx.doi.org/10.1007/s13238-022-00909-3.
Resumen
AbstractThe emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
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Morin-Dewaele, Margot, Sophie Bartier, François Berry, Rozenn Brillet, Dennis Salomón López-Molina, Công Trung Nguyễn, Pascale Maille et al. "Desloratadine, an FDA-approved cationic amphiphilic drug, inhibits SARS-CoV-2 infection in cell culture and primary human nasal epithelial cells by blocking viral entry". Scientific Reports 12, n.º 1 (6 de diciembre de 2022). http://dx.doi.org/10.1038/s41598-022-25399-5.
Resumen
AbstractThe 2019 global coronavirus (COVID-19) pandemic has brought the world to a grinding halt, highlighting the urgent need for therapeutic and preventive solutions to slow the spread of emerging viruses. The objective of this study was to assess the anti-SARS-CoV-2 effectiveness of 8 FDA-approved cationic amphiphilic drugs (CADs). SARS-CoV-2-infected Vero cells, Calu-3 cells and primary Human Nasal Epithelial Cells (HNEC) were used to investigate the effects of CADs and revealed their antiviral mode of action. Among the CADs tested, desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells. Interestingly, desloratadine was also effective against HCoV-229E and HCoV-OC43 showing that it possessed broad-spectrum anti-coronavirus activity. Investigation of its mode of action revealed that it targeted an early step of virus lifecycle and blocked SARS-CoV-2 entry through the endosomal pathway. Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment. Thus, this treatment could provide a substantial contribution to prophylaxis and systemic therapy of COVID-19 or other coronaviruses infections and requires further studies.
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Sandler, Zachary J., Mason R. Firpo, Oreoluwa S. Omoba, Michelle N. Vu, Vineet D. Menachery y Bryan C. Mounce. "Novel Ionophores Active against La Crosse Virus Identified through Rapid Antiviral Screening". Antimicrobial Agents and Chemotherapy 64, n.º 6 (13 de abril de 2020). http://dx.doi.org/10.1128/aac.00086-20.
Resumen
ABSTRACT Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families, including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (coxsackievirus, rhinovirus), flavirivuses (Zika virus), and coronaviruses (human coronavirus 229E [HCoV-229E] and Middle East respiratory syndrome CoV [MERS-CoV]). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.
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Yang, Minghui, Chunhui Li, Guoguo Ye, Chenguang Shen, Huiping Shi, Liping Zhong, Yuxin Tian et al. "Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential anti pan-coronavirus activity". Signal Transduction and Targeted Therapy 9, n.º 1 (14 de febrero de 2024). http://dx.doi.org/10.1038/s41392-024-01748-w.
Resumen
AbstractEmerging and recurrent infectious diseases caused by human coronaviruses (HCoVs) continue to pose a significant threat to global public health security. In light of this ongoing threat, the development of a broad-spectrum drug to combat HCoVs is an urgently priority. Herein, we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). These aptamers have nanomolar affinity with the nucleocapsid protein (NP) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also show excellent binding efficiency to the N proteins of both SARS, MERS, HCoV-OC43 and -NL63 with affinity KD values of 1.31 to 135.36 nM. Such aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant (BA.5) with EC50 values at 2.00 nM and 41.08 nM, respectively. The protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs (−229E and -HKU1). In conclusion, we have identified six aptamers with a high pan-coronavirus antiviral activity, which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.
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Zhao, Xu, Zhihui Cao, Xiufu Hua, Luocheng Chen, Tong Wei y Shaozhen Li. "Silver molybdate nanocrystal-reinforced high-performance anti-coronavirus composite polymer coating". AIP Advances 13, n.º 10 (1 de octubre de 2023). http://dx.doi.org/10.1063/5.0163736.
Resumen
In response to the present epidemic situation, this work proposes an anti-coronavirus composite polymer coating with nano-Ag2MoO4 as the core component to reduce the potential safety hazards caused by excessive use of disinfectants. Nano-β-Ag2MoO4 with mixed morphology was produced with industrialized preparation technology. Among them, oval nanoparticles are core components with antiviral properties, and long rod-shaped particles are used to identify whether the stirring process meets the standard. After x-ray diffraction and field emission scanning electron microscopy testing, nano-β-Ag2MoO4 stored for 4 years still meets the design requirements in terms of purity, crystal phase, shape, and scale, which solves the problem of the long-term effect of core components. In the existing water-based paint production process, the mixing process and formula of nano-β-Ag2MoO4 were explored, and the large-scale production process of anti-virus water-based paint was solved. Resistance tests against the HCoV-229E coronavirus showed that the anti-coronavirus activity rate of the nano-β-Ag2MoO4 coating at a weight concentration of 200 ppm was 99.5% within 2 h, which verified the effectiveness of the composite polymer coating.
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Rodríguez-Pulido, Miguel, Eva Calvo-Pinilla, Miryam Polo, Juan-Carlos Saiz, Raúl Fernández-González, Eva Pericuesta, Alfonso Gutiérrez-Adán, Francisco Sobrino, Miguel A. Martín-Acebes y Margarita Sáiz. "Non-coding RNAs derived from the foot-and-mouth disease virus genome trigger broad antiviral activity against coronaviruses". Frontiers in Immunology 14 (29 de marzo de 2023). http://dx.doi.org/10.3389/fimmu.2023.1166725.
Resumen
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a potentially severe respiratory disease, the coronavirus disease 2019 (COVID-19), an ongoing pandemic with limited therapeutic options. Here, we assessed the anti-coronavirus activity of synthetic RNAs mimicking specific domains in the non-coding regions of the foot-and-mouth disease virus (FMDV) genome (ncRNAs). These molecules are known to exert broad-spectrum antiviral activity in cell culture, mice and pigs effectively triggering the host innate immune response. The ncRNAs showed potent antiviral activity against SARS-CoV-2 after transfection in human intestinal Caco-2 and lung epithelium Calu-3 2B4 cells. When the in vivo efficacy of the FMDV ncRNAs was assessed in K18-hACE2 mice, administration of naked ncRNA before intranasal SARS-CoV-2 infection significantly decreased the viral load and the levels of pro-inflammatory cytokines in the lungs compared with untreated infected mice. The ncRNAs were also highly efficacious when assayed against common human HCoV-229E and porcine transmissible gastroenteritis virus (TGEV) in hepatocyte-derived Huh-7 and swine testis ST cells, respectively. These results are a proof of concept of the pan-coronavirus antiviral activity of the FMDV ncRNAs including human and animal divergent coronaviruses and potentially enhance our ability to fight future emerging variants.
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Bahgat, Dina M., Haidy A. Gad, Eman Al-Sayed, Sara H. Mahmoud, Ahmed Mostafa, Nadia M. Mahfouz, Omayma A. Eldahshan y Abdel Nasser B. Singab. "Essential Oil of Cestrum diurnum L.: GC/MS Analysis, in vitro and in silico Anti‐HCoV‐229E Effects and Inhibitory Activity against LPS‐Induced Inflammation". Chemistry & Biodiversity, 22 de febrero de 2023. http://dx.doi.org/10.1002/cbdv.202201045.
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León-Gutiérrez, Gabriela, James Edward Elste, Carlos Cabello-Gutiérrez, Cesar Millán-Pacheco, Mario H. Martínez-Gómez, Rafael Mejía-Alvarez, Vaibhav Tiwari y Armando Mejía. "A potent virucidal activity of functionalized TiO2 nanoparticles adsorbed with flavonoids against SARS-CoV-2". Applied Microbiology and Biotechnology, 11 de agosto de 2022. http://dx.doi.org/10.1007/s00253-022-12112-9.
Resumen
Abstract The coronavirus SARS-CoV-2 has caused a pandemic with > 550 millions of cases and > 6 millions of deaths worldwide. Medical management of COVID-19 relies on supportive care as no specific targeted therapies are available yet. Given its devastating effects on the economy and mental health, it is imperative to develop novel antivirals. An ideal candidate will be an agent that blocks the early events of viral attachment and cell entry, thereby preventing viral infection and spread. This work reports functionalized titanium dioxide (TiO2)-based nanoparticles adsorbed with flavonoids that block SARS-CoV-2 entry and fusion. Using molecular docking analysis, two flavonoids were chosen for their specific binding to critical regions of the SARS-CoV-2 spike glycoprotein that interacts with the host cell angiotensin-converting enzyme-2 (ACE-2) receptor. These flavonoids were adsorbed onto TiO2 functionalized nanoparticles (FTNP). This new nanoparticulate compound was assayed in vitro against two different coronaviruses; HCoV 229E and SARS-CoV-2, in both cases a clear antiviral effect was observed. Furthermore, using a reporter-based cell culture model, a potent antiviral activity is demonstrated. The adsorption of flavonoids to functionalized TiO2 nanoparticles induces a ~ threefold increase of that activity. These studies also indicate that FTNP interferes with the SARS-CoV-2 spike, impairing the cell fusion mechanism. Key points/Highlights • Unique TiO2nanoparticles displaying flavonoid showed potent anti-SARS-CoV-2 activity. • The nanoparticles precisely targeting SARS-CoV-2 were quantitatively verified by cell infectivity in vitro. • Flavonoids on nanoparticles impair the interactions between the spike glycoprotein and ACE-2 receptor. Graphical abstract
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Saiz, Maria Laura, Marta L. DeDiego, Darío López-García, Viviana Corte-Iglesias, Aroa Baragaño Raneros, Ivan Astola, Victor Asensi, Carlos López-Larrea y Beatriz Suarez-Alvarez. "Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity". Clinical Epigenetics 13, n.º 1 (11 de octubre de 2021). http://dx.doi.org/10.1186/s13148-021-01168-5.
Resumen
Abstract Background SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements. Results We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA. Conclusions Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.