Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein.
Antiviral drug
Antiviral therapy
COVID-19
Entry inhibitor
Receptor trap
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
12
07
2021
revised:
27
09
2021
accepted:
26
10
2021
pubmed:
15
11
2021
medline:
17
12
2021
entrez:
14
11
2021
Statut:
ppublish
Résumé
SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.
Identifiants
pubmed: 34774603
pii: S0166-3542(21)00187-X
doi: 10.1016/j.antiviral.2021.105197
pmc: PMC8579703
pii:
doi:
Substances chimiques
Antiviral Agents
0
Immunoglobulin G
0
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105197Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Références
Physiol Rev. 2018 Jan 1;98(1):505-553
pubmed: 29351514
J Vis Exp. 2014 Nov 04;(93):e52065
pubmed: 25407402
Cell. 2021 Jan 21;184(2):476-488.e11
pubmed: 33412089
iScience. 2022 Jan 21;25(1):103670
pubmed: 34957381
Nature. 2021 Aug;596(7871):276-280
pubmed: 34237773
Lancet Infect Dis. 2020 Aug;20(8):920-928
pubmed: 32422201
J Biol Chem. 2000 Oct 27;275(43):33238-43
pubmed: 10924499
MAbs. 2019 Nov-Dec;11(8):1341-1350
pubmed: 31556789
Clin Pharmacokinet. 2013 Sep;52(9):783-92
pubmed: 23681967
Science. 2020 Mar 13;367(6483):1260-1263
pubmed: 32075877
Sci Rep. 2020 Aug 19;10(1):14004
pubmed: 32814791
J Virol. 2004 Oct;78(19):10628-35
pubmed: 15367630
PLoS One. 2020 Aug 5;15(8):e0237295
pubmed: 32756606
Hypertension. 2010 Jan;55(1):90-8
pubmed: 19948988
Front Immunol. 2020 May 06;11:740
pubmed: 32435243
Science. 2021 Jan 8;371(6525):172-177
pubmed: 33172935
Science. 2020 Nov 13;370(6518):856-860
pubmed: 33082293
ACS Med Chem Lett. 2020 Aug 17;11(9):1667-1670
pubmed: 32934770
Clin Sci (Lond). 2020 Mar 13;134(5):543-545
pubmed: 32167153
PLoS Pathog. 2020 Aug 26;16(8):e1008820
pubmed: 32845937
Immunology. 2002 Jan;105(1):9-19
pubmed: 11849310
Front Microbiol. 2020 Jul 22;11:1800
pubmed: 32793182
Cell. 2020 Apr 16;181(2):281-292.e6
pubmed: 32155444
F1000Res. 2020 Jan 31;9:72
pubmed: 32117569
Adv Drug Deliv Rev. 2015 Aug 30;91:109-24
pubmed: 25703189
Cell. 2020 Aug 20;182(4):812-827.e19
pubmed: 32697968
N Engl J Med. 2003 May 15;348(20):1967-76
pubmed: 12690091
Proc Natl Acad Sci U S A. 2005 May 31;102(22):7988-93
pubmed: 15897467
Nature. 2020 May;581(7809):465-469
pubmed: 32235945
Nature. 2002 Jun 20;417(6891):822-8
pubmed: 12075344
J Pathol. 2004 Jun;203(2):622-30
pubmed: 15141376
Crit Care. 2017 Sep 7;21(1):234
pubmed: 28877748
MAbs. 2020 Jan-Dec;12(1):1779974
pubmed: 32633193
EMBO Mol Med. 2021 Jan 11;13(1):e12828
pubmed: 33159417
Hypertens Res. 2016 Jul;39(7):492-500
pubmed: 26888118
PLoS One. 2020 Sep 3;15(9):e0238344
pubmed: 32881907
Int J Biol Macromol. 2020 Dec 15;165(Pt B):1626-1633
pubmed: 33080267
J Pathol. 2004 Jun;203(2):631-7
pubmed: 15141377
Trends Endocrinol Metab. 2004 May-Jun;15(4):166-9
pubmed: 15109615
Nature. 2020 Nov;587(7834):340-341
pubmed: 33188367
Lancet Respir Med. 2020 Nov;8(11):1154-1158
pubmed: 33131609
J Histochem Cytochem. 2017 Jun;65(6):321-333
pubmed: 28402755
Nat Commun. 2021 Jun 21;12(1):3802
pubmed: 34155214
Circ Res. 2000 Sep 1;87(5):E1-9
pubmed: 10969042
Int J Pept. 2012;2012:256294
pubmed: 22536270
Chronic Dis Transl Med. 2020 Jun;6(2):98-105
pubmed: 32550040
Nat Struct Mol Biol. 2015 Dec;22(12):953-8
pubmed: 26595420
Cell Mol Immunol. 2021 Apr;18(4):1061-1063
pubmed: 33633321
J Cell Biol. 2009 May 18;185(4):673-84
pubmed: 19451275
Life Sci. 2020 Sep 15;257:118102
pubmed: 32687918
Nat Commun. 2020 Apr 24;11(1):2070
pubmed: 32332765
Nat Rev Immunol. 2020 Oct;20(10):633-643
pubmed: 32782358
Science. 2020 Mar 27;367(6485):1444-1448
pubmed: 32132184
Nature. 2020 Jun;582(7813):561-565
pubmed: 32365353
Nat Rev Cardiol. 2014 Jul;11(7):413-26
pubmed: 24776703
Kidney Int. 2018 Jul;94(1):114-125
pubmed: 29691064
Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28046-28055
pubmed: 33093202
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
MAbs. 2010 May-Jun;2(3):221-32
pubmed: 20404539
Cell Mol Life Sci. 2021 Jan;78(2):531-544
pubmed: 32780149
N Engl J Med. 2020 Mar 5;382(10):970-971
pubmed: 32003551
Nature. 2020 May;581(7807):215-220
pubmed: 32225176
Nature. 2021 May;593(7857):130-135
pubmed: 33684923
J Pediatric Infect Dis Soc. 2020 Jul 13;9(3):362-365
pubmed: 32441753