Bortezomib inhibits chikungunya virus replication by interfering with viral protein synthesis.
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
21
12
2019
accepted:
29
04
2020
revised:
10
06
2020
pubmed:
30
5
2020
medline:
22
7
2020
entrez:
30
5
2020
Statut:
epublish
Résumé
Chikungunya virus (CHIKV) is an alphavirus that causes a febrile illness accompanied by myalgia and arthralgia. Despite having re-emerged as a significant public health threat, there are no approved therapeutics or prophylactics for CHIKV infection. In this study, we explored the anti-CHIKV effects of proteasome inhibitors and their potential mechanism of antiviral action. A panel of proteasome inhibitors with different functional groups reduced CHIKV infectious titers in a dose-dependent manner. Bortezomib, which has been FDA-approved for multiple myeloma and mantle cell lymphoma, was further investigated in downstream studies. The inhibitory activities of bortezomib were confirmed using different cellular models and CHIKV strains. Time-of-addition and time-of-removal studies suggested that bortezomib inhibited CHIKV at an early, post-entry stage of replication. In western blot analysis, bortezomib treatment resulted in a prominent decrease in structural protein levels as early as 6 hpi. Contrastingly, nsP4 levels showed strong elevations across all time-points. NsP2 and nsP3 levels showed a fluctuating trend, with some elevations between 12 to 20 hpi. Finally, qRT-PCR data revealed increased levels of both positive- and negative-sense CHIKV RNA at late stages of infection. It is likely that the reductions in structural protein levels is a major factor in the observed reductions in virus titer, with the alterations in non-structural protein ratios potentially being a contributing factor. Proteasome inhibitors like bortezomib likely disrupt CHIKV replication through a variety of complex mechanisms and may display a potential for use as therapeutics against CHIKV infection. They also represent valuable tools for studies of CHIKV molecular biology and virus-host interactions.
Identifiants
pubmed: 32469886
doi: 10.1371/journal.pntd.0008336
pii: PNTD-D-19-02117
pmc: PMC7286522
doi:
Substances chimiques
Antiviral Agents
0
Viral Proteins
0
Bortezomib
69G8BD63PP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0008336Subventions
Organisme : Wellcome Trust
ID : 200171/Z/15/Z
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Virol. 1994 Mar;68(3):1874-85
pubmed: 8107248
Drugs. 2013 Jan;73(1):45-54
pubmed: 23338539
Viruses. 2018 Feb 08;10(2):
pubmed: 29419763
J Virol. 2018 Jun 29;92(14):
pubmed: 29743363
Proteins. 2010 Feb 1;78(2):365-80
pubmed: 19722269
Curr Pharm Des. 2013;19(22):4025-38
pubmed: 23181572
Methods Mol Biol. 2016;1426:93-103
pubmed: 27233264
Cell Death Differ. 1998 Jul;5(7):577-83
pubmed: 10200512
EMBO J. 1994 Mar 1;13(5):1058-64
pubmed: 8131740
Cancer Res. 2010 Mar 1;70(5):1970-80
pubmed: 20160034
J Virol. 2010 Mar;84(5):2352-64
pubmed: 20015978
PLoS One. 2013 Apr 10;8(4):e61444
pubmed: 23593481
Viruses. 2019 Apr 23;11(4):
pubmed: 31018496
Curr Opin Virol. 2016 Apr;17:1-10
pubmed: 26426962
PLoS Negl Trop Dis. 2015 Mar 11;9(3):e0003603
pubmed: 25760632
Virus Genes. 2016 Oct;52(5):716-21
pubmed: 27206501
Antiviral Res. 2015 Dec;124:30-42
pubmed: 26518229
Viruses. 2016 Jun 11;8(6):
pubmed: 27294951
J Virol. 2018 Jun 29;92(14):
pubmed: 29695431
Structure. 2006 Jan;14(1):63-73
pubmed: 16407066
J Med Virol. 2012 Nov;84(11):1757-70
pubmed: 22997079
Microbiol Rev. 1994 Sep;58(3):491-562
pubmed: 7968923
S Afr Med J. 1979 Jul 28;56(4):130-2
pubmed: 494034
J Virol. 2011 Jan;85(1):621-5
pubmed: 20962089
Antiviral Res. 2015 Aug;120:32-9
pubmed: 25979669
J Biol Chem. 2008 Aug 8;283(32):21899-908
pubmed: 18559340
Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8967-71
pubmed: 1924357
Curr Opin Virol. 2016 Dec;21:146-150
pubmed: 27771517
J Virol. 2012 Jul;86(13):7180-91
pubmed: 22514352
Virology. 2015 Oct;484:41-50
pubmed: 26057151
Nat Rev Microbiol. 2010 Jul;8(7):491-500
pubmed: 20551973
Virol J. 2013 Jan 28;10:36
pubmed: 23356742
J Virol. 1993 Apr;67(4):1905-15
pubmed: 8445716
J Virol. 2004 Sep;78(17):9243-56
pubmed: 15308719
J Virol. 2016 Nov 14;90(23):10600-10611
pubmed: 27654297
J Am Chem Soc. 2011 Feb 2;133(4):698-700
pubmed: 21186803
Mol Cell Biol. 2004 Nov;24(22):9848-62
pubmed: 15509788
Int J Biochem Cell Biol. 2000 Jul;32(7):747-57
pubmed: 10856705
Clin Infect Dis. 2009 Sep 15;49(6):942-8
pubmed: 19663604
Clin Cancer Res. 2011 May 1;17(9):2734-43
pubmed: 21364033
J Clin Oncol. 2006 Jul 1;24(19):3113-20
pubmed: 16754936
Plant Cell. 2010 Sep;22(9):3142-52
pubmed: 20823192
Virol Sin. 2019 Oct;34(5):572-582
pubmed: 31637631
Antimicrob Agents Chemother. 2013 Jan;57(1):155-67
pubmed: 23275491
J Virol. 2019 Feb 5;93(4):
pubmed: 30463980
J Biol Chem. 1999 Apr 2;274(14):9871-80
pubmed: 10092679
J Clin Invest. 2017 Mar 1;127(3):737-749
pubmed: 28248203
Can J Physiol Pharmacol. 2006 Jan;84(1):5-14
pubmed: 16845885
J Gen Virol. 2001 Apr;82(Pt 4):765-773
pubmed: 11257180
Virol J. 2008 Sep 26;5:108
pubmed: 18822126
Sci Rep. 2016 Feb 19;6:21406
pubmed: 26892458
J Proteomics. 2015 Apr 29;120:126-41
pubmed: 25782748
Virology. 2007 Apr 10;360(2):350-63
pubmed: 17150238
Antiviral Res. 2015 Aug;120:48-56
pubmed: 26001632
PLoS One. 2014 Aug 11;9(8):e104915
pubmed: 25111394
Trends Biochem Sci. 2000 Nov;25(11):544-8
pubmed: 11084366
Neurotoxicology. 2014 Jul;43:28-35
pubmed: 24525285
Virology. 2009 Oct 25;393(2):183-97
pubmed: 19732931
Rev Med Virol. 2013 Mar;23(2):85-96
pubmed: 22782620
mBio. 2018 Dec 11;9(6):
pubmed: 30538185
J Virol. 1998 Mar;72(3):2310-5
pubmed: 9499091
Nucleic Acids Res. 2016 May 19;44(9):4368-80
pubmed: 26984530
J Virol. 2013 Apr;87(8):4202-13
pubmed: 23365438
Expert Opin Drug Metab Toxicol. 2019 Jun;15(6):459-473
pubmed: 31104525
Int J Infect Dis. 2017 May;58:69-76
pubmed: 28288924
Antimicrob Agents Chemother. 2019 Mar 27;63(4):
pubmed: 30917980
PLoS Negl Trop Dis. 2015 Nov 13;9(11):e0004058
pubmed: 26565697
J Virol. 2001 Jan;75(1):1-10
pubmed: 11119567