Auswahl der wissenschaftlichen Literatur zum Thema „Anti-HCoV-229E activity“

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

La recherche de nouveaux antimicrobiens est actuellement cruciale pour faire face aux maladies émergentes (pandémie de la COVID-19) et à la résistance aux antibiotiques. La présente étude vise à mettre en exergue le potentiel d'espèces végétales, sélectionnées sur la base de critères écologiques et chimiotaxonomiques, comme source naturelle de composés dotés d'une grande diversité structurale et d'un éventail d'activités biologiques prometteuses. Des espèces de Juncus, collectées à partir de 3 localités en France, ont été étudiées pour leur potentiel antiviral contre les coronavirus et antibactérien contre des souches bactériennes à Gram positif. À cet effet, l'approche du fractionnement bioguidé employant des techniques séparatives conventionnelles (HPLC préparative et CPC), a été adoptée. L'étude de l'activité antivirale menée contre le coronavirus HCoV-229E a mis en évidence le pouvoir antiviral de la lutéoline isolé à partir du sous extrait AcOEt des tiges de J. acutus (localité 2). Le criblage de l'activité antibactérienne a souligné un effet remarquable du sous-extrait CH2Cl2 des rhizomes de J. inflexus (localité 3), enrichi en composés phénanthréniques, notamment contre les souches de S. aureus. Ainsi, des expériences complémentaires, permettant d'approfondir la compréhension de l'effet antibactérien de certains des composés phénanthréniques isolés, ont été réalisées en orientant le travail sur une souche de S. aureus résistante à la méticilline (SARM) et provenant d'un prélèvement sur un pied diabétique. Suite aux résultats promoteurs obtenus, le développement d'une formulation topique à base de juncusol a été initié. Des travaux portant sur la biodisponibilité de ce composé phénanthrénique ont été également réalisés par le biais d'expériences de passage de barrière intestinale in vitro au moyen de cocultures cellulaires Caco-2/HT29-MTX
To address the current challenges raised by emerging diseases (COVID-19 pandemic) and antibiotic resistance, the search for new antimicrobials has become urgent. The present study aims to highlight the potential of plant species, selected according to ecological and chemotaxonomic criteria, as a natural source of compounds with a wide structural diversity and promising biological activities. Juncus species collected from 3 localities in France were investigated for their potential antimicrobial effect against coronaviruses and Gram-positive bacterial strains. For this purpose, the approach of bioguided fractionation was adopted through the use of conventional separation techniques (preparative HPLC and CPC). The antiviral study conducted against the coronavirus HCoV-229E highlighted the antiviral potential of luteolin, a flavone that was isolated from the EtOAc sub-extract of J. acutus stems (locality 2). The screening for antibacterial activity led to the selection of the CH2Cl2 sub-extract of J. inflexus rhizomes (locality 3) for the rest of this study as this enriched-phenanthrene derivative sub-extract demonstrated a remarkable activity in particular against S. aureus strains. Additional experiments to deepen the understanding of the antibacterial effect of some of the isolated phenanthrene derivatives were performed focusing on a methicillin-resistant S. aureus strain that was isolated from a diabetic foot infection. Regarding the promising results, the developement of a topical formulation involving juncusol as an active component was initiated. Bioavailibility studies were also performed on this phenanthrene derivative through in vitro absorption and intestinal permeability experiments across Caco2/HT29-MTX co-cultured cells