scholarly journals Interferon-β-1a Inhibition of Severe Acute Respiratory Syndrome–Coronavirus 2 In Vitro When Administered After Virus Infection

2020 ◽  
Vol 222 (5) ◽  
pp. 722-725 ◽  
Author(s):  
Nicola Clementi ◽  
Roberto Ferrarese ◽  
Elena Criscuolo ◽  
Roberta Antonia Diotti ◽  
Matteo Castelli ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Virus Infection ◽  
Severe Acute Respiratory Syndrome ◽  
Clinical Management ◽  
Scientific Community ◽  
Antiviral Agents ◽  
Drug Repurposing ◽  
Potential Candidate ◽  
Interferon Β

Abstract The ongoing coronavirus disease 2019 pandemic has forced the clinical and scientific community to try drug repurposing of existing antiviral agents as a quick option against severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). Under this scenario, interferon (IFN) β-1a, whose antiviral potential is already known, and which is a drug currently used in the clinical management of multiple sclerosis, may represent as a potential candidate. In this report, we demonstrate that IFN-β-1a was highly effective in inhibiting in vitro SARS-CoV-2 replication at clinically achievable concentration when administered after virus infection.

scholarly journals Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro

2020 ◽  
Author(s):  
Norio Yamamoto ◽  
Shutoku Matsuyama ◽  
Tyuji Hoshino ◽  
Naoki Yamamoto
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Protease Inhibitor ◽  
Antiviral Agents ◽  
Specific Treatment ◽  
Potential Candidate ◽  
Serum Concentrations ◽  
Candidate Drug ◽  
Approved Drugs ◽  
Hiv 1

AbstractIn December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei Province, China. No specific treatment has been established against coronavirus disease-2019 (COVID-19) so far. Therefore, it is urgently needed to identify effective antiviral agents for the treatment of this disease, and several approved drugs such as lopinavir have been evaluated. Here, we report that nelfinavir, an HIV-1 protease inhibitor, potently inhibits replication of SARS-CoV-2. The effective concentrations for 50% and 90% inhibition (EC50 and EC90) of nelfinavir were 1.13 µM and 1.76 µM respectively, the lowest of the nine HIV-1 protease inhibitors including lopinavir. The trough and peak serum concentrations of nelfinavir were three to six times higher than EC50 of this drug. These results suggest that nelfinavir is a potential candidate drug for the treatment of COVID-19 and should be assessed in patients with COVID-19.

scholarly journals SARS Unique Domain (SUD) of Severe Acute Respiratory Syndrome Coronavirus Induces NLRP3 Inflammasome-Dependent CXCL10-Mediated Pulmonary Inflammation

2020 ◽  
Vol 21 (9) ◽  
pp. 3179 ◽  
Author(s):  
Young-Sheng Chang ◽  
Bo-Han Ko ◽  
Jyh-Cherng Ju ◽  
Hsin-Hou Chang ◽  
Su-Hua Huang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Profile Analysis ◽  
Diffuse Alveolar Damage ◽  
Pulmonary Inflammation ◽  
Antiviral Agents ◽  
Lung Epithelial Cells ◽  
Unique Domain

Severe acute respiratory syndrome–associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1β in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3−/− mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.

Effects of interferon-β on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-β treatment in patients with multiple sclerosis

2007 ◽  
Vol 14 (2) ◽  
pp. 166-176 ◽  
Author(s):  
Elke Wiesemann ◽  
Milani Deb ◽  
Corinna Trebst ◽  
Bernhard Hemmer ◽  
Martin Stangel ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Response ◽  
T Cell Activation ◽  
Mechanism Of Action ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Signaling Molecules ◽  
Interferon Β

Interferon-beta (IFN-β) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-β is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-β on the expression of co-signaling pathways (CD28—CD80/CD86, CD154—CD40, ICOS—ICOSL, PD-1—PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-β in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-β, and in vivo in whole blood samples of 32 untreated and 24 IFN-β treated MS patients, including 13 patients longitudinal. IFN-β treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-β treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-β ( P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-β upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-β in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-β treatment at early timepoints during IFN-β therapy. Multiple Sclerosis 2008; 14: 166—176. http://msj.sagepub.com

scholarly journals Functions of Coronavirus Accessory Proteins: Overview of the State of the Art

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1139
Author(s):  
Puxian Fang ◽  
Liurong Fang ◽  
Huichang Zhang ◽  
Sijin Xia ◽  
Shaobo Xiao
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Severe Acute Respiratory Syndrome ◽  
State Of The Art ◽  
Current Knowledge ◽  
Structural Proteins ◽  
Accessory Proteins ◽  
Genes Encoding ◽  
Viral Proliferation

Coronavirus accessory proteins are a unique set of proteins whose genes are interspersed among or within the genes encoding structural proteins. Different coronavirus genera, or even different species within the same coronavirus genus, encode varying amounts of accessory proteins, leading to genus- or species-specificity. Though accessory proteins are dispensable for the replication of coronavirus in vitro, they play important roles in regulating innate immunity, viral proliferation, and pathogenicity. The function of accessory proteins on virus infection and pathogenesis is an area of particular interest. In this review, we summarize the current knowledge on accessory proteins of several representative coronaviruses that infect humans or animals, including the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with an emphasis on their roles in interaction between virus and host, mainly involving stress response, innate immunity, autophagy, and apoptosis. The cross-talking among these pathways is also discussed.

scholarly journals Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ide Smets ◽  
Teresa Prezzemolo ◽  
Maya Imbrechts ◽  
Klara Mallants ◽  
Tania Mitera ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Biology ◽  
Interferon Β ◽  
Cross Sectional ◽  
Transitional B Cells ◽  
Rna Levels

Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

A pharmacogenetic study implicates NINJ2 in the response to Interferon-β in multiple sclerosis

2019 ◽  
Vol 26 (9) ◽  
pp. 1074-1082
Author(s):  
Silvia Peroni ◽  
Melissa Sorosina ◽  
Sunny Malhotra ◽  
Ferdinando Clarelli ◽  
Ana Maria Osiceanu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Meta Analysis ◽  
Luciferase Assay ◽  
Interferon Β ◽  
Pharmacogenetic Study ◽  
Optimal Drug ◽  
First Relapse ◽  
The Relationship

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients. Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role. Methods: Survival analysis was applied in three MS cohorts from different countries ( n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR. Results: Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10−4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood ( p = 7.0 × 10−6), which was confirmed in vitro ( p = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR. Conclusions: Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.

scholarly journals Baicalein and Baicalin Inhibit SARS-CoV-2 RNA-Dependent-RNA Polymerase

2021 ◽  
Vol 9 (5) ◽  
pp. 893
Author(s):  
Keivan Zandi ◽  
Katie Musall ◽  
Adrian Oo ◽  
Dongdong Cao ◽  
Bo Liang ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Specific Binding ◽  
Antiviral Agents ◽  
Potential Candidate ◽  
Rna Dependent Rna Polymerase ◽  
Antiviral Therapies ◽  
Global Pandemic ◽  
Therapeutic Development ◽  
Polymerase Inhibitor

Coronavirus Disease 2019 (COVID-19) is a deadly emerging infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Because SARS-CoV-2 is easily transmitted through the air and has a relatively long incubation time, COVID-19 has rapidly developed into a global pandemic. As there are no antiviral agents for the prevention and treatment of this severe pathogen except for remdesivir, development of antiviral therapies to treat infected individuals remains highly urgent. Here, we showed that baicalein and baicalin exhibited significant antiviral activity against SARS-CoV-2, the causative agent of COVID-19 through in vitro studies. Our data through cell-based and biochemical studies showed that both compounds act as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors directly and inhibit the activity of the SARS-CoV-2 RdRp, but baicalein was more potent. We also showed specific binding of baicalein to the SARS-CoV-2 RdRp, making it a potential candidate for further studies towards therapeutic development for COVID-19 as a selective non-nucleoside polymerase inhibitor.

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