A Novel Ebola Virus VP40 Matrix Protein-Based Screening for Identification of Novel Candidate Medical Countermeasures.
Animals
Antiviral Agents
/ chemistry
Chlorocebus aethiops
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Ebolavirus
/ drug effects
Gene Expression Regulation, Viral
/ drug effects
HEK293 Cells
Hemorrhagic Fever, Ebola
/ drug therapy
Humans
Medical Countermeasures
Molecular Structure
Nucleoproteins
/ antagonists & inhibitors
Pyrimidine Nucleosides
/ pharmacology
Vero Cells
Viral Core Proteins
/ antagonists & inhibitors
Virus Release
/ drug effects
Ebola virus
Filoviridae
MCM
Marburg virus
VP40
broad spectrum
filovirus
sangivamycin
Journal
Viruses
ISSN: 1999-4915
Titre abrégé: Viruses
Pays: Switzerland
ID NLM: 101509722
Informations de publication
Date de publication:
31 Dec 2020
31 Dec 2020
Historique:
received:
23
12
2020
accepted:
29
12
2020
entrez:
5
1
2021
pubmed:
6
1
2021
medline:
24
2
2021
Statut:
epublish
Résumé
Filoviruses, such as Ebola virus and Marburg virus, are of significant human health concern. From 2013 to 2016, Ebola virus caused 11,323 fatalities in Western Africa. Since 2018, two Ebola virus disease outbreaks in the Democratic Republic of the Congo resulted in 2354 fatalities. Although there is progress in medical countermeasure (MCM) development (in particular, vaccines and antibody-based therapeutics), the need for efficacious small-molecule therapeutics remains unmet. Here we describe a novel high-throughput screening assay to identify inhibitors of Ebola virus VP40 matrix protein association with viral particle assembly sites on the interior of the host cell plasma membrane. Using this assay, we screened nearly 3000 small molecules and identified several molecules with the desired inhibitory properties. In secondary assays, one identified compound, sangivamycin, inhibited not only Ebola viral infectivity but also that of other viruses. This finding indicates that it is possible for this new VP40-based screening method to identify highly potent MCMs against Ebola virus and its relatives.
Identifiants
pubmed: 33396288
pii: v13010052
doi: 10.3390/v13010052
pmc: PMC7824103
pii:
doi:
Substances chimiques
Antiviral Agents
0
Nucleoproteins
0
Pyrimidine Nucleosides
0
Viral Core Proteins
0
nucleoprotein VP40, Ebola virus
0
sangivamycin
18417-89-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : HHSN272200700016I
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201800013C
Pays : United States
Références
Virology. 2001 Apr 25;283(1):1-6
pubmed: 11312656
Structure. 2003 Apr;11(4):423-33
pubmed: 12679020
Cell Rep. 2015 Sep 29;12(12):2111-20
pubmed: 26365189
Virology. 2010 Jul 20;403(1):56-66
pubmed: 20444481
J Antibiot (Tokyo). 1989 Jan;42(1):102-6
pubmed: 2921215
Cell. 2013 Aug 15;154(4):763-74
pubmed: 23953110
Sci Rep. 2019 Nov 12;9(1):16588
pubmed: 31719634
Nature. 2016 Jul 7;535(7610):169-172
pubmed: 27362232
Virology. 2013 Jul 5;441(2):135-45
pubmed: 23582637
PLoS One. 2012;7(7):e39978
pubmed: 22792204
Antimicrob Agents Chemother. 1986 Mar;29(3):482-7
pubmed: 3013084
Clin Infect Dis. 2016 Nov 15;63(10):1288-1294
pubmed: 27553371
Sci Transl Med. 2012 Feb 29;4(123):123ra24
pubmed: 22378924
J Biol Chem. 2013 Feb 22;288(8):5779-89
pubmed: 23297401
Viruses. 2018 Dec 02;10(12):
pubmed: 30513823
Biochem Biophys Res Commun. 1998 Nov 18;252(2):368-72
pubmed: 9826536
Antiviral Res. 2016 Dec;136:51-59
pubmed: 27825797
Front Pharmacol. 2019 Oct 29;10:1222
pubmed: 31736746
Antiviral Res. 2011 Aug;91(2):195-208
pubmed: 21699921
Protein Sci. 2014 Nov;23(11):1519-27
pubmed: 25159197
Cancer Chemother Rep. 1967 Aug;51(4):197-200
pubmed: 4318252
Proc Soc Exp Biol Med. 1976 Mar;151(3):487-90
pubmed: 1257248
J Virol. 2015 Sep;89(18):9440-53
pubmed: 26136573
J Infect Dis. 2007 Nov 15;196 Suppl 2:S291-5
pubmed: 17940963
J Virol. 1998 Apr;72(4):2855-64
pubmed: 9525605
Virus Res. 2007 Sep;128(1-2):88-98
pubmed: 17524511
J Virol. 2010 Jul;84(14):7053-63
pubmed: 20463076
PLoS One. 2018 Mar 22;13(3):e0194880
pubmed: 29566079
J Biol Chem. 1988 Feb 5;263(4):1682-92
pubmed: 3338987
mBio. 2020 Feb 25;11(1):
pubmed: 32098814
Viruses. 2019 Mar 01;11(3):
pubmed: 30832223
Nat Rev Microbiol. 2019 May;17(5):261-263
pubmed: 30926957
Sci Rep. 2018 Jun 27;8(1):9776
pubmed: 29950600
Viruses. 2019 Apr 04;11(4):
pubmed: 30987343
J Virol. 1984 Mar;49(3):857-64
pubmed: 6321770
J Gen Virol. 1991 Mar;72 ( Pt 3):549-55
pubmed: 1706408
Cancer Res. 1981 May;41(5):1784-8
pubmed: 7214345
J Biol Chem. 1968 Jan 25;243(2):306-12
pubmed: 4865642
Biochem Pharmacol. 1980 Feb;29(3):305-10
pubmed: 7362643
J Gen Virol. 2019 Jun;100(6):911-912
pubmed: 31021739
N Engl J Med. 2019 Dec 12;381(24):2293-2303
pubmed: 31774950
J Biol Chem. 2007 May 18;282(20):15271-83
pubmed: 17371872
Cancer Res. 1974 May;34(5):1005-9
pubmed: 4823899
J Infect Dis. 2018 Nov 22;218(suppl_5):S672-S678
pubmed: 29939303
Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20803-20813
pubmed: 32764148
BMC Cancer. 2009 Feb 20;9:63
pubmed: 19232100
Antimicrob Agents Chemother. 1986 Nov;30(5):719-24
pubmed: 3800347
PLoS Med. 2016 Mar 01;13(3):e1001967
pubmed: 26930627
Antiviral Res. 2015 Aug;120:40-7
pubmed: 25986249
EMBO J. 2000 Aug 15;19(16):4228-36
pubmed: 10944105
Nature. 2016 Mar 17;531(7594):381-5
pubmed: 26934220
PLoS Pathog. 2006 Sep;2(9):e99
pubmed: 17009868
Biochem Biophys Res Commun. 2014 Feb 7;444(2):135-40
pubmed: 24434142
J Infect Dis. 2018 Nov 22;218(suppl_5):S612-S626
pubmed: 29860496
Med Sci (Paris). 2020 Nov;36(11):1027-1033
pubmed: 33151849
Nat Rev Microbiol. 2019 Oct;17(10):593-606
pubmed: 31341272
PLoS Negl Trop Dis. 2016 May 18;10(5):e0004709
pubmed: 27191161
J Infect Dis. 2019 Jun 19;220(2):195-202
pubmed: 30788508
Lancet Infect Dis. 2020 Sep;20(9):e231-e237
pubmed: 32563280
Nat Immunol. 2002 Mar;3(3):265-71
pubmed: 11828323
Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449-463
pubmed: 28769016
Sci Transl Med. 2013 Jun 19;5(190):190ra79
pubmed: 23785035
J Med Chem. 2014 Mar 27;57(6):2247-57
pubmed: 24564608
PLoS One. 2016 Nov 30;11(11):e0166318
pubmed: 27902714
J Virol. 2005 Feb;79(3):1898-905
pubmed: 15650213
EMBO J. 2000 Dec 15;19(24):6732-41
pubmed: 11118208
Curr Eye Res. 1987 Jan;6(1):255-7
pubmed: 3030647
PLoS Negl Trop Dis. 2017 Apr 12;11(4):e0005540
pubmed: 28403145
Clin Pharmacol Ther. 1970 Jan-Feb;11(1):3-40
pubmed: 4983384
Antiviral Res. 2014 Jul;107:102-9
pubmed: 24815087
J Biol Chem. 2008 Dec 12;283(50):34580-7
pubmed: 18927075
J Med Chem. 1984 Mar;27(3):285-92
pubmed: 6699874
Subcell Biochem. 2018;88:73-94
pubmed: 29900493
Nature. 2014 Apr 17;508(7496):402-5
pubmed: 24590073