Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
25 05 2022
25 05 2022
Historique:
received:
13
12
2021
accepted:
17
05
2022
revised:
12
05
2022
entrez:
25
5
2022
pubmed:
26
5
2022
medline:
28
5
2022
Statut:
epublish
Résumé
The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug's ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.
Identifiants
pubmed: 35614039
doi: 10.1038/s41419-022-04961-z
pii: 10.1038/s41419-022-04961-z
pmc: PMC9130985
doi:
Substances chimiques
Antiviral Agents
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Raloxifene Hydrochloride
4F86W47BR6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
498Informations de copyright
© 2022. The Author(s).
Références
Lancet. 2020 Feb 22;395(10224):565-574
pubmed: 32007145
Oncologist. 2000;5(5):388-92
pubmed: 11040275
Molecules. 2021 Feb 04;26(4):
pubmed: 33557115
Emerg Infect Dis. 2006 Jan;12(1):128-33
pubmed: 16494729
Cell Transplant. 2021 Jan-Dec;30:963689721991477
pubmed: 33522308
Science. 2021 May 21;372(6544):815-821
pubmed: 33853970
J Hepatol. 2012 Dec;57(6):1186-92
pubmed: 22889955
BMJ Open. 2020 Oct 6;10(10):e040129
pubmed: 33028563
Mol Psychiatry. 2015 Jun;20(6):685-94
pubmed: 25980345
J Clin Oncol. 2008 Sep 1;26(25):4151-9
pubmed: 18757329
Shock. 2006 Mar;25(3):214-26
pubmed: 16552352
Cell Death Differ. 2022 Jan;29(1):156-166
pubmed: 34404919
Int J Womens Health. 2010 Aug 09;1:11-20
pubmed: 21072271
Kidney Int. 2003 Jun;63(6):2269-74
pubmed: 12753317
JAMA. 2006 Jun 21;295(23):2727-41
pubmed: 16754727
J Genet Genomics. 2021 Dec;48(12):1111-1121
pubmed: 34954396
Nature. 2021 Apr;592(7854):438-443
pubmed: 33690265
Endocrinology. 2020 Sep 1;161(9):
pubmed: 32730568
N Engl J Med. 2006 Jul 13;355(2):125-37
pubmed: 16837676
Mol Pharm. 2021 Mar 1;18(3):754-771
pubmed: 33464914
Cell. 2020 Aug 20;182(4):812-827.e19
pubmed: 32697968
Climacteric. 2022 Feb;25(1):56-59
pubmed: 34169801
J Virol. 2005 Aug;79(15):9470-9
pubmed: 16014910
Molecules. 2020 Mar 19;25(6):
pubmed: 32204528
Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7001-7003
pubmed: 32165541
J Microbiol. 2021 Feb;59(2):124-131
pubmed: 33527314
MedComm (2020). 2022 Mar 16;3(1):e126
pubmed: 35317190
Emerg Microbes Infect. 2014 Dec;3(12):e84
pubmed: 26038505
Eur Cytokine Netw. 2007 Sep;18(3):148-53
pubmed: 17823083
FASEB J. 2020 Nov;34(11):14103-14119
pubmed: 32965736
Science. 2021 Apr 9;372(6538):
pubmed: 33658326
Asian Pac J Trop Med. 2021;14(1):5-9
pubmed: 33828641
Antimicrob Agents Chemother. 2020 Jul 22;64(8):
pubmed: 32482672
Microbes Infect. 2013 Jan;15(1):45-55
pubmed: 23103222
Signal Transduct Target Ther. 2021 Dec 14;6(1):420
pubmed: 34907154
Front Pharmacol. 2020 Sep 25;11:561334
pubmed: 33101023
J Clin Endocrinol Metab. 2004 Aug;89(8):3841-6
pubmed: 15292315
Signal Transduct Target Ther. 2020 Mar 27;5(1):33
pubmed: 32296069
Front Pharmacol. 2020 Jul 15;11:1085
pubmed: 32765279
Cell Death Dis. 2021 Aug 5;12(8):773
pubmed: 34354045
Proc Natl Acad Sci U S A. 2020 Dec 11;:
pubmed: 33310900
Endocr Rev. 2007 Aug;28(5):521-74
pubmed: 17640948
Antiviral Res. 2013 Apr;98(1):19-26
pubmed: 23415884
Semin Oncol. 2020 Oct;47(5):335-340
pubmed: 32660890
Nat Rev Microbiol. 2021 Mar;19(3):141-154
pubmed: 33024307
Nephrol Dial Transplant. 2020 Jun 1;35(6):1071-1072
pubmed: 32291449
Hum Reprod Update. 2005 Jul-Aug;11(4):411-23
pubmed: 15817524
Am J Physiol Lung Cell Mol Physiol. 2016 Mar 1;310(5):L415-25
pubmed: 26684252
BMB Rep. 2020 Mar;53(3):166-171
pubmed: 31964466
Nat Rev Microbiol. 2019 Mar;17(3):181-192
pubmed: 30531947
Lancet. 2020 Feb 15;395(10223):497-506
pubmed: 31986264
J Med Virol. 2020 Nov;92(11):2283-2285
pubmed: 32343429
Euro Surveill. 2021 Apr;26(16):
pubmed: 33890566
Ann Oncol. 2021 May;32(5):676-677
pubmed: 33524477
Science. 2020 Mar 27;367(6485):1444-1448
pubmed: 32132184
JAMA. 2021 Apr 6;325(13):1318-1320
pubmed: 33635317
Trends Immunol. 2011 Aug;32(8):380-7
pubmed: 21752713
Drugs. 2000 Aug;60(2):379-411
pubmed: 10983739
J Enzyme Inhib Med Chem. 2021 Dec;36(1):147-153
pubmed: 33430659
FEBS Open Bio. 2012 Aug 22;2:279-83
pubmed: 23650611
mBio. 2018 Dec 18;9(6):
pubmed: 30563895
Eur J Pharmacol. 2002 Jan 11;434(3):141-9
pubmed: 11779577
J Biomol Struct Dyn. 2022 Feb;40(3):982-994
pubmed: 32930050
In Vivo. 2020 Sep-Oct;34(5):3027-3028
pubmed: 32871847
Cell Immunol. 2015 Apr;294(2):63-9
pubmed: 25682174
Int J Mol Sci. 2020 Jul 21;21(14):
pubmed: 32708196
Virus Res. 2008 Apr;133(1):33-44
pubmed: 17451829
BMJ. 2021 Feb 18;372:n494
pubmed: 33602668
J Autoimmun. 2020 Jul;111:102468
pubmed: 32317220
JAMA. 2021 Apr 6;325(13):1261-1262
pubmed: 33571363
Mayo Clin Proc. 2020 Oct;95(10):2189-2203
pubmed: 33012349
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Signal Transduct Target Ther. 2021 Jun 11;6(1):233
pubmed: 34117216
Front Immunol. 2016 Jan 06;6:635
pubmed: 26779182
Front Immunol. 2020 Oct 07;11:576745
pubmed: 33117379
Expert Rev Anticancer Ther. 2009 Jan;9(1):51-60
pubmed: 19105706
FEBS Open Bio. 2021 May;11(5):1452-1464
pubmed: 33822489
Hypertens Res. 2021 Jul;44(7):882-884
pubmed: 33536584
Lancet Infect Dis. 2022 Jan;22(1):35-42
pubmed: 34461056
Mutat Res. 2005 Dec 11;591(1-2):247-63
pubmed: 16083919
Adv Virus Res. 2021;110:59-102
pubmed: 34353482
Int J Mol Sci. 2020 Jul 28;21(15):
pubmed: 32731361