Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury.
Acute Lung Injury
/ drug therapy
Amitriptyline
/ administration & dosage
Animals
Azacitidine
/ administration & dosage
Calcitriol
/ administration & dosage
Disease Models, Animal
Drug Repositioning
Female
Flavin-Adenine Dinucleotide
/ administration & dosage
Humans
Influenza A Virus, H5N1 Subtype
/ physiology
Influenza, Human
/ complications
Lung
/ immunology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
15
11
2019
accepted:
21
01
2020
entrez:
17
3
2020
pubmed:
17
3
2020
medline:
7
7
2020
Statut:
epublish
Résumé
Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre- and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an anti-neoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.
Identifiants
pubmed: 32176725
doi: 10.1371/journal.ppat.1008341
pii: PPATHOGENS-D-19-02141
pmc: PMC7075543
doi:
Substances chimiques
Flavin-Adenine Dinucleotide
146-14-5
Amitriptyline
1806D8D52K
Calcitriol
FXC9231JVH
Azacitidine
M801H13NRU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008341Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Cell Biochem. 2018 Sep 22;:
pubmed: 30242880
Nat Commun. 2014 May 06;5:3594
pubmed: 24800825
Am J Respir Cell Mol Biol. 2011 May;44(5):725-38
pubmed: 21531958
Nature. 2016 Jun 14;534(7607):314-6
pubmed: 27306171
Curr Protein Pept Sci. 2016;17(4):332-42
pubmed: 26119506
Methods Mol Biol. 2007;356:319-50
pubmed: 16988414
Mol Med Rep. 2017 Nov;16(5):7432-7438
pubmed: 28944831
J Cell Sci. 2015 Aug 15;128(16):3094-105
pubmed: 26116574
Clin Infect Dis. 2006 Sep 15;43(6):748-56
pubmed: 16912951
Cell Res. 2012 Mar;22(3):528-38
pubmed: 22025253
Cell Res. 2013 Apr;23(4):577-80
pubmed: 23419516
Am J Respir Cell Mol Biol. 2016 Sep;55(3):419-28
pubmed: 27089175
Mol Med Rep. 2016 Feb;13(2):1186-94
pubmed: 26675943
Nature. 2007 Oct 11;449(7163):721-5
pubmed: 17914358
Front Immunol. 2019 Jan 29;10:60
pubmed: 30761132
Oncologist. 2007 Oct;12(10):1247-52
pubmed: 17962618
Int Immunopharmacol. 2016 Mar;32:55-61
pubmed: 26800098
Respir Res. 2010 Mar 20;11:33
pubmed: 20302656
Nucleic Acids Res. 2014 Jan;42(Database issue):D1091-7
pubmed: 24203711
Assay Drug Dev Technol. 2015 Dec;13(10):638-49
pubmed: 26192013
PLoS Pathog. 2019 Mar 18;15(3):e1007601
pubmed: 30883607
Bull World Health Organ. 1979;57(2):275-9
pubmed: 373903
Cell Res. 2013 Feb;23(2):300-2
pubmed: 23208422
J Trauma Acute Care Surg. 2015 May;78(5):980-7
pubmed: 25909419
JACC Basic Transl Sci. 2017 Oct 30;2(5):613-625
pubmed: 30062175
Toxicol Mech Methods. 2015;25(5):417-23
pubmed: 26360969
Mol Med Rep. 2017 Dec;16(6):9652-9658
pubmed: 29039541
Leuk Lymphoma. 1999 Oct;35(3-4):347-54
pubmed: 10706459
N Engl J Med. 1997 Feb 20;336(8):525-33
pubmed: 9036306
Mol Biosyst. 2012 Apr;8(4):1297-303
pubmed: 22307679
Trends Immunol. 2009 Dec;30(12):574-84
pubmed: 19864182
Antioxid Redox Signal. 2014 Jun 10;20(17):2681-91
pubmed: 24295151
Int J Biochem Cell Biol. 2018 Sep;102:117-127
pubmed: 30010012
Am J Respir Cell Mol Biol. 2013 Sep;49(3):368-83
pubmed: 23590305