scholarly journals Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2082
Author(s):  
Yuyong Zhou ◽  
Karen A. Gammeltoft ◽  
Andrea Galli ◽  
Anna Offersgaard ◽  
Ulrik Fahnøe ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Ion Channel ◽  
Viral Entry ◽  
Selectivity Index ◽  
Viral Escape ◽  
Human Hepatoma ◽  
Entry Level ◽  
Ion Channel Inhibitors ◽  
Post Entry

We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2.

scholarly journals Inhibitors of Protein Glycosylation Are Active against the Coronavirus Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 808
Author(s):  
Sreejith Rajasekharan ◽  
Rafaela Milan Bonotto ◽  
Lais Nascimento Alves ◽  
Yvette Kazungu ◽  
Monica Poggianella ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Marked Decrease ◽  
Treatment Options ◽  
Protein Glycosylation ◽  
Investigational Drug ◽  
Entry Level ◽  
Relevant Role ◽  
Post Entry ◽  
Niemann Pick

Repurposing clinically available drugs to treat the new coronavirus disease 2019 (COVID-19) is an urgent need in the course of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) pandemic, as very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases, such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated in the micromolar range for SARS-CoV-2 in vitro. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious viruses. The mechanism resides in the inhibitory activity toward α-glucosidases that are involved in the early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. Indeed, the antiviral potential of protein glycosylation inhibitors against SARS-CoV-2 is further highlighted by the low-micromolar activity of the investigational drug Celgosivir. These data point to a relevant role of this approach for the treatment of COVID-19.

scholarly journals Anti-severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) potency of Mefloquine as an entry inhibitor in vitro

2020 ◽  
Author(s):  
Kaho Shionoya ◽  
Masako Yamasaki ◽  
Shoya Iwanami ◽  
Yusuke Ito ◽  
Shuetsu Fukushi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Combined Treatment ◽  
Entry Inhibitor ◽  
Economic Damage ◽  
Virus Elimination ◽  
Viral Attachment ◽  
Approved Drugs ◽  
Treatment Dosage

AbstractCoronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 μM, IC90 = 2.31 μM, and IC99 = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.

scholarly journals Mefloquine, a Potent Anti-severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Drug as an Entry Inhibitor in vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaho Shionoya ◽  
Masako Yamasaki ◽  
Shoya Iwanami ◽  
Yusuke Ito ◽  
Shuetsu Fukushi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Combined Treatment ◽  
Entry Inhibitor ◽  
Economic Damage ◽  
Virus Elimination ◽  
Viral Attachment ◽  
Approved Drugs ◽  
Treatment Dosage

Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 μM, IC90 = 2.31 μM, and IC99 = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.

scholarly journals Neutralizing Human Antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 Isolated from a Human Synthetic Fab Phage Display Library

2021 ◽  
Vol 22 (4) ◽  
pp. 1913
Author(s):  
Yu Jung Kim ◽  
Min Ho Lee ◽  
Se-Ra Lee ◽  
Hyo-Young Chung ◽  
Kwangmin Kim ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Phage Display ◽  
Viral Entry ◽  
Phage Display Library ◽  
Cross Reactivity ◽  
Spike Protein ◽  
Receptor Protein ◽  
In Vitro Assays ◽  
Global Threat

Since it was first reported in Wuhan, China, in 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic outbreak resulting in a tremendous global threat due to its unprecedented rapid spread and an absence of a prophylactic vaccine or therapeutic drugs treating the virus. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is a key player in the viral entry into cells through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor protein, and the RBD has therefore been crucial as a drug target. In this study, we used phage display to develop human monoclonal antibodies (mAbs) that neutralize SARS-CoV-2. A human synthetic Fab phage display library was panned against the RBD of the SARS-CoV-2 spike protein (SARS-2 RBD), yielding ten unique Fabs with moderate apparent affinities (EC50 = 19–663 nM) for the SARS-2 RBD. All of the Fabs showed no cross-reactivity to the MERS-CoV spike protein, while three Fabs cross-reacted with the SARS-CoV spike protein. Five Fabs showed neutralizing activities in in vitro assays based on the Fabs’ activities antagonizing the interaction between the SARS-2 RBD and ACE2. Reformatting the five Fabs into immunoglobulin Gs (IgGs) greatly increased their apparent affinities (KD = 0.08–1.0 nM), presumably due to the effects of avidity, without compromising their non-aggregating properties and thermal stability. Furthermore, two of the mAbs (D12 and C2) significantly showed neutralizing activities on pseudo-typed and authentic SARS-CoV-2. Given their desirable properties and neutralizing activities, we anticipate that these human anti-SARS-CoV-2 mAbs would be suitable reagents to be further developed as antibody therapeutics to treat COVID-19, as well as for diagnostics and research tools.

scholarly journals Specific combinations of ion channel inhibitors reduce excessive Ca2+ influx as a consequence of oxidative stress and increase neuronal and glial cell viability in vitro

Neuroscience ◽  
2016 ◽  
Vol 339 ◽  
pp. 450-462 ◽  
Author(s):  
Ryan L. O’Hare Doig ◽  
Carole A. Bartlett ◽  
Nicole M. Smith ◽  
Stuart I. Hodgetts ◽  
Sarah A. Dunlop ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Ion Channel ◽  
Glial Cell ◽  
Ion Channel Inhibitors

scholarly journals Hemin as a novel candidate for treating COVID-19 via heme oxygenase-1 induction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dong-Hwi Kim ◽  
Hee-Seop Ahn ◽  
Hyeon-Jeong Go ◽  
Da-Yoon Kim ◽  
Jae-Hyeong Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Severe Acute Respiratory Syndrome ◽  
Heme Oxygenase ◽  
Death Rate ◽  
Expression Vector ◽  
Viral Infections ◽  
Selectivity Index ◽  
Heme Oxygenase 1 ◽  
Antiviral Effects

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease-19 (COVID-19). More than 143 million cases of COVID-19 have been reported to date, with the global death rate at 2.13%. Currently, there are no licensed therapeutics for controlling SARS-CoV-2 infection. The antiviral effects of heme oxygenase-1 (HO-1), a cytoprotective enzyme that inhibits the inflammatory response and reduces oxidative stress, have been investigated in several viral infections. To confirm whether HO-1 suppresses SARS-CoV-2 infection, we assessed the antiviral activity of hemin, an effective and safe HO-1 inducer, in SARS-CoV-2 infection. We found that treatment with hemin efficiently suppressed SARS-CoV-2 replication (selectivity index: 249.7012). Besides, the transient expression of HO-1 using an expression vector also suppressed the growth of the virus in cells. Free iron and biliverdin, which are metabolic byproducts of heme catalysis by HO-1, also suppressed the viral infection. Additionally, hemin indirectly increased the expression of interferon-stimulated proteins known to restrict SARS-CoV-2 replication. Overall, the findings suggested that HO-1, induced by hemin, effectively suppressed SARS-CoV-2 in vitro. Therefore, HO-1 could be potential therapeutic candidate for COVID-19.

scholarly journals Antiviral effect of Archidendron pauciflorum leaves extract to hepatitis C virus: An in vitro study in JFH-1 strain

2018 ◽  
Vol 27 (1) ◽  
pp. 12-8 ◽  
Author(s):  
Sri Hartati ◽  
Chie Aoki ◽  
Muhammad Hanafi ◽  
Marissa Angelina ◽  
Pratiwi Soedarmono ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Methanol Extract ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Hcv Genotype ◽  
Butanol Fraction ◽  
Post Entry

Background: Hepatitis C virus (HCV) is a leading cause of chronic liver diseases. Drug resistance to the regimen is also increasing. Hence, there is a need for new anti-HCV agents that are less toxic and more efficacious. The aim of this study is to evaluate the  possibility of A. pauciflorum extracts can be a antiviral drug.Methods: Huh-7it cells were infected with the HCV genotype 2a strain JFH-I in the presence of methanol extracts of Archidenron pauciflorum. The methanol extract further partition used n-hexane, ethyl acetate, n-butanol, and water showed in which butanol extracts exerted the strongest IC50 (6.3 g/ml). Further, the butanol fraction was fractionated and yielded into 13 fractions.Results: The methanol extract of the leaves of A. pauciflorum exhibited concentration dependent inhibition against the JFH1 strain of HCV genotype 2a with an IC50 is 72.5 μg/ml. The butanol fraction exhibited the highest anti-HCV activity with an IC50 is 6.3 μg/ml. The butanol fraction was fractionated which yielded 13 fractions. Fractions 5 and 13 exhibited high anti-HCV activities with IC50 is 5.0 μg/ml and 8.5 μg/ml and a time-of-addition study demonstrated that fraction 5 inhibited viral infection at the post-entry step, whereas fraction 13 primarily inhibited the viral entry step.Conclusion: The extract A. pauciflorum can be used as a herbal-based antiviral drug.

scholarly journals Antibody Neutralization of an Influenza Virus that Uses Neuraminidase for Receptor Binding

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 597 ◽  
Author(s):  
Lauren E. Gentles ◽  
Hongquan Wan ◽  
Maryna C. Eichelberger ◽  
Jesse D. Bloom
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Viral Entry ◽  
Active Site ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Viral Escape ◽  
Single Cycle ◽  
Escape Mutants

Influenza virus infection elicits antibodies against the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Because HA is essential for viral entry, antibodies targeting HA often potently neutralize the virus in single-cycle infection assays. However, antibodies against NA are not potently neutralizing in such assays, since NA is dispensable for single-cycle infection. Here we show that a modified influenza virus that depends on NA for receptor binding is much more sensitive than a virus with receptor-binding HA to neutralization by some anti-NA antibodies. Specifically, a virus with a receptor-binding G147R N1 NA and a binding-deficient HA is completely neutralized in single-cycle infections by an antibody that binds near the NA active site. Infection is also substantially inhibited by antibodies that bind NA epitopes distant from the active site. Finally, we demonstrate that this modified virus can be used to efficiently select mutations in NA that escape antibody binding, a task that can be laborious with typical influenza viruses that are not well neutralized by anti-NA antibodies. Thus, viruses dependent on NA for receptor binding allow for sensitive in vitro detection of antibodies binding near the catalytic site of NA and enable the selection of viral escape mutants.

scholarly journals In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

2021 ◽  
Vol 10 (14) ◽  
pp. 3007
Author(s):  
Mathieu Gendrot ◽  
Priscilla Jardot ◽  
Océane Delandre ◽  
Manon Boxberger ◽  
Julien Andreani ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Antiviral Activity ◽  
Viral Entry ◽  
Low Cost ◽  
Antiviral Drug ◽  
Effective Concentration ◽  
Rt Pcr ◽  
Post Entry ◽  
Median Effective Concentration

A new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19), which emerged in Wuhan, China in December 2019, has spread worldwide. Currently, very few treatments are officially recommended against SARS-CoV-2. Identifying effective, low-cost antiviral drugs with limited side effects that are affordable immediately is urgently needed. Methylene blue, a synthesized thiazine dye, may be a potential antiviral drug. Antiviral activity of methylene blue used alone or in combination with several antimalarial drugs or remdesivir was assessed against infected Vero E6 cells infected with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6). Effects both on viral entry in the cell and on post-entry were also investigated. After 48 h post-infection, the viral replication was estimated by RT-PCR. The median effective concentration (EC50) and 90% effective concentration (EC90) of methylene blue against IHUMI-3 were 0.41 ± 0.34 µM and 1.85 ± 1.41 µM, respectively; 1.06 ± 0.46 µM and 5.68 ± 1.83 µM against IHUMI-6. Methylene blue interacted at both entry and post-entry stages of SARS-CoV-2 infection in Vero E6 cells as retrieved for hydroxychloroquine. The effects of methylene blue were additive with those of quinine, mefloquine and pyronaridine. The combinations of methylene blue with chloroquine, hydroxychloroquine, desethylamodiaquine, piperaquine, lumefantrine, ferroquine, dihydroartemisinin and remdesivir were antagonist. These results support the potential interest of methylene blue to treat COVID-19.

scholarly journals Antibody neutralization of an influenza virus that uses neuraminidase for receptor binding

2020 ◽  
Author(s):  
Lauren E. Gentles ◽  
Hongquan Wan ◽  
Maryna C. Eichelberger ◽  
Jesse D. Bloom
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Viral Entry ◽  
Active Site ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Viral Escape ◽  
Single Cycle ◽  
Escape Mutants

AbstractInfluenza virus infection elicits antibodies against the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Because HA is essential for viral entry, antibodies targeting HA often potently neutralize the virus in single-cycle infection assays. But antibodies against NA are not potently neutralizing in such assays, since NA is dispensable for single-cycle infection. Here we show that a modified influenza virus that depends on NA for receptor binding is much more sensitive than a virus with receptor-binding HA to neutralization by some anti-NA antibodies. Specifically, virus with a receptor-binding G147R N1 NA and a binding-deficient HA is completely neutralized in single-cycle infections by an antibody that binds near the NA active site. Infection is also substantially inhibited by antibodies that bind NA epitopes distant from the active site. Finally, we demonstrate that this modified virus can be used to efficiently select mutations in NA that escape antibody binding, a task that can be laborious with typical influenza viruses that are not well-neutralized by anti-NA antibodies. Thus, viruses dependent on NA for receptor binding allow for sensitive in vitro detection of antibodies binding near the catalytic site of NA and enable selection of viral escape mutants.

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