Peptidomimetic inhibitors of TMPRSS2 block SARS-CoV-2 infection in cell culture.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
08 07 2022
08 07 2022
Historique:
received:
26
10
2021
accepted:
21
06
2022
entrez:
8
7
2022
pubmed:
9
7
2022
medline:
14
7
2022
Statut:
epublish
Résumé
The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic TMPRSS2 inhibitors. Molecular docking studies identified peptidomimetic binders of the TMPRSS2 catalytic site, which were synthesized and coupled to an electrophilic serine trap. The compounds inhibit TMPRSS2 while demonstrating good off-target selectivity against selected coagulation proteases. Lead candidates are stable in blood serum and plasma for at least ten days. Finally, we show that selected peptidomimetics inhibit SARS-CoV-2 Spike-driven pseudovirus entry and authentic SARS-CoV-2 infection with comparable efficacy as camostat mesylate. The peptidomimetic TMPRSS2 inhibitors also prevent entry of recent SARS-CoV-2 variants of concern Delta and Omicron BA.1. In sum, our study reports antivirally active and stable TMPRSS2 inhibitors with prospects for further preclinical and clinical development as antiviral agents against SARS-CoV-2 and other TMPRSS2-dependent viruses.
Identifiants
pubmed: 35804152
doi: 10.1038/s42003-022-03613-4
pii: 10.1038/s42003-022-03613-4
pmc: PMC9270327
doi:
Substances chimiques
Peptidomimetics
0
Serine Endopeptidases
EC 3.4.21.-
TMPRSS2 protein, human
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
681Informations de copyright
© 2022. The Author(s).
Références
Antiviral Res. 2020 Sep;181:104882
pubmed: 32738255
Aging (Albany NY). 2020 Dec 31;13(1):27-60
pubmed: 33472167
J Chem Theory Comput. 2015 Aug 11;11(8):3696-713
pubmed: 26574453
J Med Chem. 2012 Jul 26;55(14):6582-94
pubmed: 22716043
Cell. 2020 Jul 23;182(2):429-446.e14
pubmed: 32526206
ChemMedChem. 2016 Mar 17;11(6):585-99
pubmed: 26889658
EClinicalMedicine. 2021 May;35:100865
pubmed: 33937735
Lancet Infect Dis. 2021 Sep;21(9):1246-1256
pubmed: 33857406
Mol Cell Biol. 2006 Feb;26(3):965-75
pubmed: 16428450
Pharmacol Res. 2020 Jul;157:104837
pubmed: 32334052
Methods Mol Biol. 2008;494:177-86
pubmed: 18726574
J Med Chem. 2005 Mar 24;48(6):1984-2008
pubmed: 15771442
Biochem J. 2013 Jun 1;452(2):331-43
pubmed: 23527573
Hypertension. 2015 Apr;65(4):793-9
pubmed: 25691619
J Chem Inf Model. 2011 Apr 25;51(4):829-36
pubmed: 21434641
J Virol. 2019 Oct 15;93(21):
pubmed: 31391268
Cell. 2021 Apr 29;184(9):2384-2393.e12
pubmed: 33794143
Nat Commun. 2021 Mar 19;12(1):1726
pubmed: 33741941
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
pubmed: 10592235
J Virol. 2010 Oct;84(19):10016-25
pubmed: 20631123
PLoS One. 2010 Sep 10;5(9):
pubmed: 20844765
J Virol. 2013 Jun;87(11):6150-60
pubmed: 23536651
J Med Chem. 2006 Dec 28;49(26):7781-91
pubmed: 17181160
Intern Emerg Med. 2020 Aug;15(5):801-812
pubmed: 32458206
Nat Protoc. 2007;2(12):3247-56
pubmed: 18079725
Int J Mol Sci. 2022 Jan 25;23(3):
pubmed: 35163273
J Mol Biol. 1996 Aug 23;261(3):470-89
pubmed: 8780787
J Virol. 2008 Sep;82(17):8942-6
pubmed: 18562527
Gut. 2020 Jun;69(6):997-1001
pubmed: 32241899
Science. 2021 Apr 9;372(6538):
pubmed: 33658326
Nat Microbiol. 2020 Apr;5(4):562-569
pubmed: 32094589
J Virol. 2010 Dec;84(24):12658-64
pubmed: 20926566
Cell Chem Biol. 2019 Nov 21;26(11):1559-1572.e9
pubmed: 31543462
J Med Chem. 2019 Jan 24;62(2):480-490
pubmed: 30571119
Nature. 2021 Apr;592(7855):616-622
pubmed: 33567448
JAMA Cardiol. 2020 Nov 1;5(11):1281-1285
pubmed: 32730555
Cell. 2021 Apr 29;184(9):2348-2361.e6
pubmed: 33730597
Biochem J. 2005 Aug 15;390(Pt 1):125-36
pubmed: 15839837
Medchemcomm. 2019 Jul 18;10(9):1646-1655
pubmed: 31803403
J Virol. 2013 Dec;87(23):12552-61
pubmed: 24027332
Physiol Rev. 2020 Jul 1;100(3):1065-1075
pubmed: 32216698
Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303
pubmed: 29788355
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4860-4
pubmed: 21741839
J Med Chem. 2002 Sep 26;45(20):4419-32
pubmed: 12238922
EBioMedicine. 2021 Mar;65:103255
pubmed: 33676899
J Virol. 2019 Mar 5;93(6):
pubmed: 30626688
Nat Commun. 2020 Mar 27;11(1):1620
pubmed: 32221306
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
pubmed: 4202581
J Chem Inf Model. 2015 Nov 23;55(11):2324-37
pubmed: 26479676
Nat Med. 2020 Jul;26(7):1017-1032
pubmed: 32651579
Cell. 2020 Oct 29;183(3):739-751.e8
pubmed: 32991842
Haematologica. 2009 Jun;94(6):840-9
pubmed: 19377077
Annu Rev Cell Dev Biol. 2011;27:213-35
pubmed: 21721945
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
J Cheminform. 2014 Apr 03;6:12
pubmed: 24694216
PLoS Pathog. 2013;9(12):e1003774
pubmed: 24348248
Nat Rev Immunol. 2020 Jun;20(6):363-374
pubmed: 32346093
ACS Med Chem Lett. 2012 Apr 11;3(7):530-4
pubmed: 24900505
Nat Chem Biol. 2022 Jun 8;:
pubmed: 35676539
Gastroenterology. 2020 May;158(6):1831-1833.e3
pubmed: 32142773