scholarly journals Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2

2021 ◽  
Author(s):  
Jean-Selim Driouich ◽  
Maxime Cochin ◽  
Franck Touret ◽  
Paul-Remi Petit ◽  
Magali Gilles ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Clinical Evaluation ◽  
Airway Epithelium ◽  
Active Metabolite ◽  
Clinical Evidence ◽  
Oral Treatment ◽  
Standard Formulation ◽  
Virus Challenge ◽  
Human Airway Epithelium

To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.

scholarly journals An approach to testing undiluted e-cigarette aerosol in vitro using 3D reconstituted human airway epithelium

2019 ◽  
Vol 54 ◽  
pp. 391-401 ◽  
Author(s):  
E. Bishop ◽  
L. Haswell ◽  
J. Adamson ◽  
S. Costigan ◽  
D. Thorne ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Human Airway ◽  
Human Airway Epithelium

An in vitro model of human airway epithelium (EpiAirway) for in vitro metabolism and toxicity screening

2007 ◽  
Vol 172 ◽  
pp. S79 ◽  
Author(s):  
Patrick Hayden ◽  
Joseph Kubilus ◽  
Helena Kandárová ◽  
Mitchell Klausner ◽  
George Jackson ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
In Vitro Model ◽  
In Vitro Metabolism ◽  
Toxicity Screening ◽  
Human Airway ◽  
Human Airway Epithelium ◽  
Vitro Model

scholarly journals HTCC as a Polymeric Inhibitor of SARS-CoV-2 and MERS-CoV

2020 ◽  
Author(s):  
Aleksandra Milewska ◽  
Ying Chi ◽  
Artur Szczepanski ◽  
Emilia Barreto-Duran ◽  
Agnieszka Dabrowska ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Ex Vivo ◽  
Multiorgan Failure ◽  
Highly Pathogenic ◽  
Modified Chitosan ◽  
Human Airway Epithelium ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
Global And Local

Among seven coronaviruses that infect humans, three (SARS-CoV, MERS-CoV, and the newly identified SARS-CoV-2) are associated with a severe, life-threatening respiratory infection and multiorgan failure. We previously proposed that the cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) is a potent inhibitor of HCoV-NL63. Next, we demonstrated the broad-spectrum antiviral activity of the compound, as it inhibited all low pathogenic human coronaviruses (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1). Here, using in vitro and ex vivo model of human airway epithelium, we show that HTCC effectively blocks MERS-CoV and SARS-CoV-2 infection. We also confirmed the mechanism of action for these two viruses, showing that the polymer blocks the virus entry to the host cell by interaction with the S protein. IMPORTANCE The beginning of 2020 brought us information about the novel coronavirus emerging in China. Rapid research resulted in the characterization of the pathogen, which appeared to be a member of the SARS-like cluster, commonly seen in bats. Despite the global and local efforts, the virus escaped the health care measures and rapidly spread in China and later globally, officially causing a pandemic and global crisis in March 2020. At present, different scenarios are being written to contain the virus, but the development of novel anticoronavirals for all highly pathogenic coronaviruses remains the major challenge. Here, we describe the antiviral activity of previously developed by us HTCC compound, which may be used as a potential inhibitor of currently circulating highly pathogenic coronaviruses – SARS-CoV-2 and MERS-CoV.

scholarly journals DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis

2009 ◽  
Vol 65 (2) ◽  
pp. 275-284 ◽  
Author(s):  
Gallen B. Triana-Baltzer ◽  
Maria Babizki ◽  
Michael C. W. Chan ◽  
Adam C. N. Wong ◽  
Laura M. Aschenbrenner ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Fusion Protein ◽  
Airway Epithelium ◽  
Influenza Virus Infection ◽  
Human Airway ◽  
Human Airway Epithelium ◽  
Pharmacodynamic Analysis

scholarly journals Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model

2015 ◽  
Vol 44 (2) ◽  
pp. 220-226 ◽  
Author(s):  
D. Rivera-Burgos ◽  
U. Sarkar ◽  
A. R. Lever ◽  
M. J. Avram ◽  
J. R. Coppeta ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Metabolite Profiling ◽  
Lung Model ◽  
Human Airway ◽  
Human Airway Epithelium

scholarly journals Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

2001 ◽  
Vol 45 (4) ◽  
pp. 1086-1093 ◽  
Author(s):  
Kanyin E. Zhang ◽  
Ellen Wu ◽  
Amy K. Patick ◽  
Bradley Kerr ◽  
Mark Zorbas ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Active Metabolite ◽  
Parent Drug ◽  
Hiv Reverse Transcriptase ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Hiv 1

ABSTRACT Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K i = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3′-methoxy-4′-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 μM and the M8 concentrations ranged from 0.55 to 1.96 μM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 μM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

scholarly journals The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins

2020 ◽  
Vol 19 (5) ◽  
pp. 793-807 ◽  
Author(s):  
Olivier Touzelet ◽  
Lindsay Broadbent ◽  
Stuart D. Armstrong ◽  
Waleed Aljabr ◽  
Elaine Cloutman-Green ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Airway Epithelium ◽  
Ex Vivo ◽  
Lymphocyte Activation ◽  
Respiratory Epithelium ◽  
Airway Epithelial ◽  
Pediatric Airway ◽  
Antiviral Responses ◽  
Syncytial Virus

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.

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