scholarly journals Nafamostat-interferon-alpha combination suppresses SARS-CoV-2 infection in vitro and in vivo

2021 ◽  
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yo ◽  
Hilde Lysvand ◽  
Gunnveig Grodeland ◽  
Nicolas Legrand ◽  
...  
Keyword(s):  
Public Health ◽  
Patient Outcome ◽  
Cell Culture ◽  
Antiviral Activity ◽  
Critical Role ◽  
Low Doses ◽  
Important Mediator ◽  
The World

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here we address these challenges by combining Pegasys (IFNa) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNa and that both Serpin E1 and camostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

scholarly journals Nafamostat–Interferon-α Combination Suppresses SARS-CoV-2 Infection In Vitro and In Vivo by Cooperatively Targeting Host TMPRSS2

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1768
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yao ◽  
Hilde Lysvand ◽  
Gunnveig Grødeland ◽  
Nicolas Legrand ◽  
...  
Keyword(s):  
Public Health ◽  
Patient Outcome ◽  
Cell Culture ◽  
Critical Role ◽  
Interferon Α ◽  
Low Doses ◽  
Important Mediator ◽  
The World

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

scholarly journals In vitro activity of human recombinant alpha-2b interferon against SARS-CoV-2 virus

2021 ◽  
Vol 66 (2) ◽  
pp. 123-128
Author(s):  
S. Ya. Loginova ◽  
V. N. Shсhukina ◽  
S. V. Savenko ◽  
S. V. Borisevich
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Viral Infections ◽  
Complete Suppression ◽  
Antiviral Efficacy ◽  
Prevention And Treatment ◽  
Proven Efficacy ◽  
High Antiviral Activity

Introduction. The pandemic spread of a new coronavirus infection, COVID-19, has caused a global emergency and attracted the attention of public health professionals and the population of all countries. A significant increase in the number of new cases of SARS-CoV-2 infection demonstrates the urgency of finding drugs effective against this pathogen.The aim of this work was to evaluate the in vitro antiviral efficacy of human recombinant alpha-2b interferon (IFN-α2b) against SARS-CoV-2 virus.Material and methods. The experiments had been carried out on Vero Cl008, the continuous line of African green monkey (Chlorocebus sabaeus) kidney cells. The effectiveness of the drugs was assessed by the suppression of viral reproduction in vitro. The biological activity was determined using titration of a virus-containing suspension in a Vero Cl008 cell culture by the formation of negative colonies.Results. The antiviral efficacy of the IFN-α2b-based medications, which have a high safety profile and proven efficacy in the prevention and treatment of influenza and acute respiratory viral infections (ARVI), has been studied against the new pandemic SARS-CoV-2 virus in vitro experiments in Vero C1008 cell culture. IFN-α2b effectively inhibits the reproduction of the virus when applied both 24 hrs before and 2 hrs after infection. In the IFN-α2b concentration range 102–106 IU/ml a complete suppression of the reproduction of the SARS-CoV-2 virus had been demonstrated.Discussion. IFN-α2b demonstrated in vitro high antiviral activity against SARS-CoV-2. In addition, the substance has a high chemotherapeutic index (>1000).Conclusion. Medications for intranasal use based on IFN-α2b have high antiviral activity and are promising drugs for in vivo study in terms of prevention and treatment of COVID-19.

scholarly journals The in vitro and in vivo potency of CT-P59 against Delta and its associated variants of SARS-CoV-2

2021 ◽  
Author(s):  
Dong-Kyun Ryu ◽  
Hye-Min Woo ◽  
Bobin Kang ◽  
Hanmi Noh ◽  
Jong-In Kim ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Respiratory Tract ◽  
Animal Studies ◽  
Antiviral Effect ◽  
The World ◽  
Symptom Remission ◽  
Challenge Experiment ◽  
Reduced Activity

The Delta variant originally from India is rapidly spreading across the world and causes to resurge infections of SARS-CoV-2. We previously reported that CT-P59 presented its in vivo potency against Beta and Gamma variants, despite its reduced activity in cell experiments. Yet, it remains uncertain to exert the antiviral effect of CT-P59 on the Delta and its associated variants (L452R). To tackle this question, we carried out cell tests and animal study. CT-P59 showed reduced antiviral activity but enabled neutralization against Delta, Epsilon, and Kappa variants in cells. In line with in vitro results, the mouse challenge experiment with the Delta variant substantiated in vivo potency of CT-P59 showing symptom remission and virus abrogation in the respiratory tract. Collectively, cell and animal studies showed that CT-P59 is effective against the Delta variant infection, hinting that CT-P59 has therapeutic potency for patients infected with Delta and its associated variants.

Antiviral activities of pyridine fused and pyridine containing heterocycles, a review (From 2000 to 2020)

2021 ◽  
Vol 21 ◽  
Author(s):  
Seyedeh Roya Alizadeh ◽  
Mohammad Ali Ebrahimzadeh
Keyword(s):  
Antiviral Activity ◽  
Biological Activities ◽  
Critical Role ◽  
Antiviral Agents ◽  
Rnase H ◽  
Pyridine Derivatives ◽  
Action Mechanism ◽  
Syncytial Virus

: Heterocyclic compounds play a critical role in medicinal chemistry and many available drugs contain heterocyclic rings. A six-membered heterocyclic compound pyridine showed various applications that acts as an important solvent, reagent, and precursor in agrochemicals and pharmaceuticals. Due to the increase of drug resistance, there is an obvious medical need to develop new antiviral agents. Various derivatives of pyridine scaffold display abroad biological activities such as anti-microbial, anti-viral, antioxidant, anti-diabetic, anti-cancer, anti-malaria, analgesic and anti-inflammatory activities, psychopharmacological antagonistic, anti-amoebic agents, and anti-thrombic activity. Due to the high importance of pyridine derivatives, in the present review, we tried to collect and classify many pyridine derivatives based on their structures from 2000 to 2020. Pyridine derivatives were classified into two general categories including pyridine containing heterocycles and pyridine fused rings. Structure-activity relationship (SAR) and the action mechanism of derivatives were also investigated. According to the recent studies, these derivatives exhibited good antiviral activity against different types of viruses such as the human immunodeficiency viruses (HIV), the hepatitis C virus (HCV), the hepatitis B virus (HBV), Respiratory syncytial virus (RSV), and Cytomegalovirus (CMV). These derivatives inhibited viral application with different action mechanism such as RT inhibition, polymerase inhibition, Inhibition of RNase H activity, inhibition of maturation, inhibition of the viral thymidine kinase, AAK1 (Adaptor-Associated Kinase 1) inhibition, GAK (Cyclin G-associated kinase) inhibition, inhibition of post-integrational event, inhibition of HDAC6, CCR5 antagonistic activity, DNA and RNA replication inhibition, gene expression inhibition, cellular NF-jB signaling pathway and neuraminidase (NA) inhibition, protein synthesis inhibition, and generally inhibition of viral replication cycle. This paper summarily expressed the past and present results about the discovery of novel lead compounds with good antiviral activity. Studies exhibited that almost all of the evaluations were performed by way of in vitro testing and is necessary to investigate in vivo and clinical testing for having better evaluations in the future. We believe that pyridine derivatives can be used as promising antiviral agents and needs to perform more broad investigations in this field.

scholarly journals Continuous Reassortment of Clade 2.3.4.4 H5N6 Highly Pathogenetic Avian Influenza Viruses Demonstrating High Risk to Public Health

Pathogens ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 670 ◽  
Author(s):  
Huanan Li ◽  
Qian Li ◽  
Bo Li ◽  
Yang Guo ◽  
Jinchao Xing ◽  
...  
Keyword(s):  
Public Health ◽  
High Risk ◽  
Avian Influenza ◽  
Migratory Birds ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Avian Influenza Viruses ◽  
The World

Since it firstly emerged in China in 2013, clade 2.3.4.4 H5N6 highly pathogenic avian influenza viruses (HPAIVs) has rapidly replaced predominant H5N1 to become the dominant H5 subtype in China, especially in ducks. Not only endemic in China, it also crossed the geographical barrier and emerged in South Korea, Japan, and Europe. Here, we analyzed the genetic properties of the clade 2.3.4.4 H5N6 HPAIVs with full genome sequences available online together with our own isolates. Phylogenetic analysis showed that clade 2.3.4.4 H5N6 HPAIVs continuously reassorted with local H5, H6, and H7N9/H9N2. Species analysis reveals that aquatic poultry and migratory birds became the dominant hosts of H5N6. Adaption to aquatic poultry might help clade 2.3.4.4 H5N6 better adapt to migratory birds, thus enabling it to become endemic in China. Besides, migratory birds might help clade 2.3.4.4 H5N6 transmit all over the world. Clade 2.3.4.4 H5N6 HPAIVs also showed a preference for α2,6-SA receptors when compared to other avian origin influenza viruses. Experiments in vitro and in vivo revealed that clade 2.3.4.4 H5N6 HPAIVs exhibited high replication efficiency in both avian and mammal cells, and it also showed high pathogenicity in both mice and chickens, demonstrating high risk to public health. Considering all the factors together, adaption to aquatic poultry and migratory birds helps clade 2.3.4.4 H5N6 overcome the geographical isolation, and it has potential to be the next influenza pandemic in the world, making it worthy of our attention.

scholarly journals Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

2014 ◽  
Vol 58 (7) ◽  
pp. 4042-4047 ◽  
Author(s):  
Amedeo De Nicolò ◽  
Marco Simiele ◽  
Andrea Calcagno ◽  
Adnan Mohamed Abdi ◽  
Stefano Bonora ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Antiviral Effect ◽  
Antiretroviral Drugs ◽  
Low Doses ◽  
Once Daily ◽  
Intracellular Concentrations

ABSTRACTProtease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n= 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n= 40), lopinavir-ritonavir 400 and 100 mg twice daily (n= 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n= 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, furtherin vitroandin vivostudies of the RTV antiviral effect are warranted.

scholarly journals Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation

2017 ◽  
Vol 22 (5) ◽  
pp. 583-601 ◽  
Author(s):  
P. Marc D. Watson ◽  
Edel Kavanagh ◽  
Gary Allenby ◽  
Matthew Vassey
Keyword(s):  
Cell Culture ◽  
Drug Discovery ◽  
Glial Cell ◽  
Critical Role ◽  
3D Culture ◽  
Cell Types ◽  
Culture Systems ◽  
Cellular Environment

Neurodegeneration and neuroinflammation are key features in a range of chronic central nervous system (CNS) diseases such as Alzheimer’s and Parkinson’s disease, as well as acute conditions like stroke and traumatic brain injury, for which there remains significant unmet clinical need. It is now well recognized that current cell culture methodologies are limited in their ability to recapitulate the cellular environment that is present in vivo, and there is a growing body of evidence to show that three-dimensional (3D) culture systems represent a more physiologically accurate model than traditional two-dimensional (2D) cultures. Given the complexity of the environment from which cells originate, and their various cell–cell and cell–matrix interactions, it is important to develop models that can be controlled and reproducible for drug discovery. 3D cell models have now been developed for almost all CNS cell types, including neurons, astrocytes, microglia, and oligodendrocyte cells. This review will highlight a number of current and emerging techniques for the culture of astrocytes and microglia, glial cell types with a critical role in neurodegenerative and neuroinflammatory conditions. We describe recent advances in glial cell culture using electrospun polymers and hydrogel macromolecules, and highlight how these novel culture environments influence astrocyte and microglial phenotypes in vitro, as compared to traditional 2D systems. These models will be explored to illuminate current trends in the techniques used to create 3D environments for application in research and drug discovery focused on astrocytes and microglial cells.

scholarly journals Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1294
Author(s):  
Robert Koban ◽  
Markus Neumann ◽  
Philipp P. Nelson ◽  
Heinz Ellerbrok
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Virus Replication ◽  
3D Culture ◽  
Human Keratinocytes ◽  
Infection Model ◽  
Cowpox Virus ◽  
Primary Human Keratinocytes

Repurposing of approved drugs that target host functions also important for virus replication promises to overcome the shortage of antiviral therapeutics. Mostly, virus biology including initial screening of antivirals is studied in conventional monolayer cells. The biology of these cells differs considerably from infected tissues. 3D culture models with characteristics of human tissues may reflect more realistically the in vivo events during infection. We screened first, second, and third generation epidermal growth factor receptor (EGFR)-inhibitors with different modes of action and the EGFR-blocking monoclonal antibody cetuximab in a 3D cell culture infection model with primary human keratinocytes and cowpox virus (CPXV) for antiviral activity. Antiviral activity of erlotinib and osimertinib was nearly unaffected by the cultivation method similar to the virus-directed antivirals tecovirimat and cidofovir. In contrast, the host-directed inhibitors afatinib and cetuximab were approx. 100-fold more efficient against CPXV in the 3D infection model, similar to previous results with gefitinib. In summary, inhibition of EGFR-signaling downregulates virus replication comparable to established virus-directed antivirals. However, in contrast to virus-directed inhibitors, in vitro efficacy of host-directed antivirals might be seriously affected by cell cultivation. Results obtained for afatinib and cetuximab suggest that screening of such drugs in standard monolayer culture might underestimate their potential as antivirals.

scholarly journals Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524)

2021 ◽  
Author(s):  
Michael K Lo ◽  
Punya Shrivastava-Ranjan ◽  
Payel Chatterjee ◽  
Mike Flint ◽  
James R Beadle ◽  
...  
Keyword(s):  
Public Health ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Airway Epithelial Cells ◽  
Health Concern ◽  
Airway Epithelial ◽  
Public Health Concern ◽  
Small Airway Epithelial Cells

The intravenous administration of remdesivir for COVID-19 confines its utility to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524) against viruses that cause diseases of human public health concern, including SARS-CoV-2. ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had near-equivalent activity to remdesivir in primary-like human small airway epithelial cells. Our results warrant investigation of ODBG-P-RVn efficacy in vivo.

scholarly journals Antivirals against human and animal Coronaviruses: different approach in SARS-CoV-2 treatment

2020 ◽  
Author(s):  
Igor Andrade Santos ◽  
Victória Riquena Grosche ◽  
Robinson Sabino-Silva ◽  
Ana Carolina Gomes Jardim
Keyword(s):  
Public Health ◽  
Antiviral Activity ◽  
Biological Activities ◽  
Severe Disease ◽  
Novel Therapies ◽  
Global Public Health ◽  
Novel Approaches

Coronaviruses (CoVs) is a group of viruses from Coronaviridae family which are able to infect human and animals, causing mild to severe disease. The recently emergence of SARS-CoV-2, worldwide classified as a pandemic disease represent a threat to global public health. Associated with the high transmissibility, the lack of vaccine and antivirals drugs demonstrates the need to develop novel therapies to treat infected patients. This review aims to summarize compounds from 2005 up to now with already described antiviral activity in vitro and in vivo to human and animal CoVs. These compounds may present as a source of molecules with potent biological activities which could be further investigated for their use as novel approaches against SARS-CoV-2.

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