Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

AbstractRemdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.

Download Full-text

Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets

10.21203/rs.3.rs-662905/v1 ◽

2021 ◽

Author(s):

Richard Plemper ◽

Robert Cox ◽

Josef Wolf ◽

Carolin Lieber ◽

Julien Sourimant ◽

...

Keyword(s):

Cell Culture ◽

Animal Model ◽

Oral Administration ◽

Therapeutic Benefit ◽

Early Administration ◽

Relevant Animal Model ◽

Orally Bioavailable ◽

Plasma Metabolite ◽

Oral Prodrug ◽

Daily Oral Administration

Abstract Remdesivir is the only small-molecule antiviral approved to date for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterized the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibited SARS-CoV-2, including variants of concern (VoC) in cell culture. Oral GS-621763 was efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduced SARS-CoV-2 burden to near-undetectable levels. When dosed therapeutically against VoC P.1 gamma (γ), oral GS-621763 blocked virus replication and prevented transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.

Download Full-text

Somatic cell hemoglobin modulates nitrogen oxide metabolism in the human airway epithelium

Scientific Reports ◽

10.1038/s41598-021-94782-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nadzeya Marozkina ◽

Laura Smith ◽

Yi Zhao ◽

Joe Zein ◽

James F. Chmiel ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Nitrogen Oxides ◽

Airway Epithelium ◽

Airflow Obstruction ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelium ◽

Human Airway Epithelial Cells

AbstractEndothelial hemoglobin (Hb)α regulates endothelial nitric oxide synthase (eNOS) biochemistry. We hypothesized that Hb could also be expressed and biochemically active in the ciliated human airway epithelium. Primary human airway epithelial cells, cultured at air–liquid interface (ALI), were obtained by clinical airway brushings or from explanted lungs. Human airway Hb mRNA data were from publically available databases; or from RT-PCR. Hb proteins were identified by immunoprecipitation, immunoblot, immunohistochemistry, immunofluorescence and liquid chromatography- mass spectrometry. Viral vectors were used to alter Hbβ expression. Heme and nitrogen oxides were measured colorimetrically. Hb mRNA was expressed in human ciliated epithelial cells. Heme proteins (Hbα, β, and δ) were detected in ALI cultures by several methods. Higher levels of airway epithelial Hbβ gene expression were associated with lower FEV1 in asthma. Both Hbβ knockdown and overexpression affected cell morphology. Hbβ and eNOS were apically colocalized. Binding heme with CO decreased extracellular accumulation of nitrogen oxides. Human airway epithelial cells express Hb. Higher levels of Hbβ gene expression were associated with airflow obstruction. Hbβ and eNOS were colocalized in ciliated cells, and heme affected oxidation of the NOS product. Epithelial Hb expression may be relevant to human airways diseases.

Download Full-text

Stimulation of aquaporin-5 and transepithelial water permeability in human airway epithelium by hyperosmotic stress

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-006-0157-3 ◽

2006 ◽

Vol 453 (6) ◽

pp. 777-785 ◽

Cited By ~ 15

Author(s):

Peter Steen Pedersen ◽

Thomas Hartig Braunstein ◽

Anders Jørgensen ◽

Per Leganger Larsen ◽

Niels-Henrik Holstein-Rathlou ◽

...

Keyword(s):

Water Permeability ◽

Airway Epithelium ◽

Hyperosmotic Stress ◽

Aquaporin 5 ◽

Human Airway ◽

Human Airway Epithelium ◽

Stimulation Of

Download Full-text

Functional expression of connexin30 and connexin31 in the polarized human airway epithelium

Differentiation ◽

10.1111/j.1432-0436.2007.00157.x ◽

2007 ◽

Vol 75 (5) ◽

pp. 382-392 ◽

Cited By ~ 23

Author(s):

Ludovic Wiszniewski ◽

Javier Sanz ◽

Isabelle Scerri ◽

Elena Gasparotto ◽

Tecla Dudez ◽

...

Keyword(s):

Airway Epithelium ◽

Functional Expression ◽

Human Airway ◽

Human Airway Epithelium

Download Full-text

Reconstituted human airway epithelium 3D-model to assess the impact of indoor air pollutants on the inflammatory response

Toxicology Letters ◽

10.1016/j.toxlet.2013.05.184 ◽

2013 ◽

Vol 221 ◽

pp. S112 ◽

Cited By ~ 1

Author(s):

Sophie Grellet ◽

Isabelle Momas ◽

Nathalie Seta ◽

Gaëlle Bardet ◽

Sophie Achard

Keyword(s):

Inflammatory Response ◽

Indoor Air ◽

Airway Epithelium ◽

Air Pollutants ◽

3D Model ◽

Human Airway ◽

Human Airway Epithelium ◽

Indoor Air Pollutants ◽

The Impact

Download Full-text

Chemokine Transcripts as Targets of the RNA-Binding Protein HuR in Human Airway Epithelium

The Journal of Immunology ◽

10.4049/jimmunol.0903634 ◽

2011 ◽

Vol 186 (4) ◽

pp. 2482-2494 ◽

Cited By ~ 45

Author(s):

Jinshui Fan ◽

Faoud T. Ishmael ◽

Xi Fang ◽

Allen Myers ◽

Chris Cheadle ◽

...

Keyword(s):

Airway Epithelium ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Human Airway ◽

Human Airway Epithelium

Download Full-text

RECOMBINANT SENDAI VIRUS FOR EFFICIENT GENE TRANSFER TO HUMAN AIRWAY EPITHELIUM

Experimental Lung Research ◽

10.1080/01902140490266501 ◽

2004 ◽

Vol 30 (2) ◽

pp. 83-96 ◽

Cited By ~ 7

Author(s):

Olaf Pinkenburg ◽

Claus Vogelmeier ◽

Sascha Bossow ◽

Wolfgang J. Neubert ◽

Raimund B. Lutz ◽

...

Keyword(s):

Gene Transfer ◽

Airway Epithelium ◽

Sendai Virus ◽

Human Airway ◽

Human Airway Epithelium ◽

Efficient Gene

Download Full-text

Altered Receptor Specificity and Cell Tropism of D222G Hemagglutinin Mutants Isolated from Fatal Cases of Pandemic A(H1N1) 2009 Influenza Virus

Journal of Virology ◽

10.1128/jvi.01639-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 12069-12074 ◽

Cited By ~ 148

Author(s):

Yan Liu ◽

Robert A. Childs ◽

Tatyana Matrosovich ◽

Stephen Wharton ◽

Angelina S. Palma ◽

...

Keyword(s):

Airway Epithelium ◽

Influenza A ◽

Cell Tropism ◽

Ciliated Cells ◽

Fatal Disease ◽

Receptor Binding Site ◽

Bronchial Epithelial ◽

Human Airway Epithelium ◽

Influenza A H1n1 ◽

Microarray Analyses

ABSTRACT Mutations in the receptor-binding site of the hemagglutinin of pandemic influenza A(H1N1) 2009 viruses have been detected sporadically. An Asp222Gly (D222G) substitution has been associated with severe or fatal disease. Here we show that 222G variants infected a higher proportion of ciliated cells in cultures of human airway epithelium than did viruses with 222D or 222E, which targeted mainly nonciliated cells. Carbohydrate microarray analyses showed that 222G variants bind a broader range of α2-3-linked sialyl receptor sequences of a type expressed on ciliated bronchial epithelial cells and on epithelia within the lung. These features of 222G mutants may contribute to exacerbation of disease.

Download Full-text