Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections.
Antiviral Agents
/ pharmacology
Cell Line
Drug Synergism
Humans
Interferon-alpha
/ pharmacology
Lung
/ drug effects
Metabolome
/ drug effects
Organoids
RNA, Viral
/ biosynthesis
SARS-CoV-2
/ drug effects
Signal Transduction
/ drug effects
Transcriptome
/ drug effects
Virus Replication
/ drug effects
Viruses
/ classification
SARS-CoV-2
antiviral drug combination
hepatitis C virus
hepatitis E virus
human immunodeficiency virus
influenza A virus
interferon-alpha
Journal
Viruses
ISSN: 1999-4915
Titre abrégé: Viruses
Pays: Switzerland
ID NLM: 101509722
Informations de publication
Date de publication:
11 12 2021
11 12 2021
Historique:
received:
12
11
2021
revised:
03
12
2021
accepted:
08
12
2021
entrez:
28
12
2021
pubmed:
29
12
2021
medline:
7
1
2022
Statut:
epublish
Résumé
There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.
Sections du résumé
BACKGROUND
There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects.
METHODS
Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro.
RESULTS
While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies.
CONCLUSIONS
Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.
Identifiants
pubmed: 34960758
pii: v13122489
doi: 10.3390/v13122489
pmc: PMC8705725
pii:
doi:
Substances chimiques
Antiviral Agents
0
Interferon-alpha
0
RNA, Viral
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Estonian Research Council
ID : MOBTT39
Références
Int J Infect Dis. 2020 Apr;93:268-276
pubmed: 32081774
Chin Med J (Engl). 2005 Mar 20;118(6):493-6
pubmed: 15788131
Lancet Respir Med. 2021 Dec;9(12):1365-1376
pubmed: 34672949
Viruses. 2020 Oct 18;12(10):
pubmed: 33080984
Basic Clin Pharmacol Toxicol. 2021 Feb;128(2):204-212
pubmed: 33176395
Front Physiol. 2020 Sep 18;11:555039
pubmed: 33071815
Immunity. 2019 Apr 16;50(4):907-923
pubmed: 30995506
Drugs. 1997 Apr;53(4):657-80
pubmed: 9098665
Viruses. 2021 Sep 04;13(9):
pubmed: 34578348
BMC Infect Dis. 2020 Oct 2;20(1):723
pubmed: 33008327
Sci Rep. 2014 Jun 05;4:5193
pubmed: 24898935
N Engl J Med. 2021 Feb 25;384(8):693-704
pubmed: 32678530
Nature. 2021 Jul;595(7866):283-288
pubmed: 34010947
N Engl J Med. 2021 Feb 11;384(6):497-511
pubmed: 33264556
Viruses. 2020 Jun 13;12(6):
pubmed: 32545799
PLoS Pathog. 2020 Jul 29;16(7):e1008737
pubmed: 32726355
Antiviral Res. 2020 Jul;179:104811
pubmed: 32360182
Lancet. 2020 May 30;395(10238):1695-1704
pubmed: 32401715
Antiviral Res. 2016 Sep;133:23-31
pubmed: 27451344
Viruses. 2018 Aug 12;10(8):
pubmed: 30103549
PLoS Pathog. 2021 Aug 9;17(8):e1009427
pubmed: 34370799
J Thromb Haemost. 2016 Jan;14(1):28-39
pubmed: 26565070
Viruses. 2021 Apr 09;13(4):
pubmed: 33918958
Nat Immunol. 2011 Jun 05;12(7):624-30
pubmed: 21642987
Front Immunol. 2020 May 15;11:1061
pubmed: 32574262
Science. 2020 Oct 23;370(6515):
pubmed: 32972995
Lancet. 2017 Sep 16;390(10100):1211-1259
pubmed: 28919117
Bioinformatics. 2017 Aug 1;33(15):2413-2415
pubmed: 28379339
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Biochem Pharmacol. 2021 Jan;183:114316
pubmed: 33152343
Trends Microbiol. 2018 Jun;26(6):510-524
pubmed: 29157967
Viruses. 2017 Sep 25;9(10):
pubmed: 28946654
Sci Transl Med. 2020 Apr 29;12(541):
pubmed: 32253226
Nature. 2021 Mar;591(7848):92-98
pubmed: 33307546
J Biol Chem. 2020 Oct 9;295(41):13958-13964
pubmed: 32587093
Int J Biol Sci. 2013;9(2):200-8
pubmed: 23459883
Science. 2020 Oct 23;370(6515):
pubmed: 32972996
Sci Rep. 2021 Apr 13;11(1):8059
pubmed: 33850184
Br J Pharmacol. 2021 Jun;178(11):2339-2350
pubmed: 33825201
FEBS J. 2017 Jan;284(2):222-236
pubmed: 27860276
Lancet Respir Med. 2021 May;9(5):498-510
pubmed: 33556319
Cell Host Microbe. 2020 Jun 10;27(6):870-878
pubmed: 32464097
Bioinformatics. 2020 Jun 1;36(11):3602-3604
pubmed: 32119072
J Virol. 2021 Jan 29;:
pubmed: 33514628
Cytokine. 2020 Sep;133:153847
pubmed: 27595182
Trends Immunol. 2015 Mar;36(3):124-38
pubmed: 25704559
Lancet. 2014 Dec 6;384(9959):2053-63
pubmed: 24954675
J Infect Dis. 2019 Mar 15;219(7):1026-1034
pubmed: 30428049
Lipids Health Dis. 2019 Nov 27;18(1):207
pubmed: 31775868
Nucleic Acids Res. 2020 Jul 2;48(W1):W488-W493
pubmed: 32246720
Nat Microbiol. 2019 Jun;4(6):914-924
pubmed: 30936491
PLoS Biol. 2021 Feb 25;19(2):e3001091
pubmed: 33630831
N Engl J Med. 2002 Sep 26;347(13):975-82
pubmed: 12324553
Emerg Microbes Infect. 2019;8(1):1763-1776
pubmed: 31826721
Curr Opin Virol. 2011 Dec;1(6):487-96
pubmed: 22347990
Antiviral Res. 2020 Jun;178:104791
pubmed: 32275914
Nature. 2020 Jul;583(7816):469-472
pubmed: 32408336
Cancers (Basel). 2020 Jun 25;12(6):
pubmed: 32630560
Sci Rep. 2017 Mar 23;7:44676
pubmed: 28333153
Lancet Respir Med. 2021 Feb;9(2):196-206
pubmed: 33189161
Int J Antimicrob Agents. 2020 Apr;55(4):105933
pubmed: 32147516
Viruses. 2017 Aug 12;9(8):
pubmed: 28805681
FEBS J. 2017 Jan;284(2):218-221
pubmed: 28121076
Lancet. 2017 Sep 16;390(10100):1260-1344
pubmed: 28919118
Science. 2020 Aug 7;369(6504):718-724
pubmed: 32661059
Viruses. 2019 Oct 18;11(10):
pubmed: 31635418
Pharm World Sci. 2005 Dec;27(6):423-31
pubmed: 16341948
Drug Discov Today. 2019 May;24(5):1224-1228
pubmed: 30980905