An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

Abstract The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding doma...

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Autores principales:	Shiho Tanaka, Gard Nelson, C. Anders Olson, Oleksandr Buzko, Wendy Higashide, Annie Shin, Marcos Gonzalez, Justin Taft, Roosheel Patel, Sofija Buta, Ashley Richardson, Dusan Bogunovic, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, Patrick Soon-Shiong
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4c4a182a1df54a5cb62090f68bebf693
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spelling	oai:doaj.org-article:4c4a182a1df54a5cb62090f68bebf6932021-12-02T17:41:31ZAn ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants10.1038/s41598-021-91809-92045-2322https://doaj.org/article/4c4a182a1df54a5cb62090f68bebf6932021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91809-9https://doaj.org/toc/2045-2322Abstract The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.Shiho TanakaGard NelsonC. Anders OlsonOleksandr BuzkoWendy HigashideAnnie ShinMarcos GonzalezJustin TaftRoosheel PatelSofija ButaAshley RichardsonDusan BogunovicPatricia SpilmanKayvan NiaziShahrooz RabizadehPatrick Soon-ShiongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shiho Tanaka Gard Nelson C. Anders Olson Oleksandr Buzko Wendy Higashide Annie Shin Marcos Gonzalez Justin Taft Roosheel Patel Sofija Buta Ashley Richardson Dusan Bogunovic Patricia Spilman Kayvan Niazi Shahrooz Rabizadeh Patrick Soon-Shiong An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants
description	Abstract The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.
format	article
author	Shiho Tanaka Gard Nelson C. Anders Olson Oleksandr Buzko Wendy Higashide Annie Shin Marcos Gonzalez Justin Taft Roosheel Patel Sofija Buta Ashley Richardson Dusan Bogunovic Patricia Spilman Kayvan Niazi Shahrooz Rabizadeh Patrick Soon-Shiong
author_facet	Shiho Tanaka Gard Nelson C. Anders Olson Oleksandr Buzko Wendy Higashide Annie Shin Marcos Gonzalez Justin Taft Roosheel Patel Sofija Buta Ashley Richardson Dusan Bogunovic Patricia Spilman Kayvan Niazi Shahrooz Rabizadeh Patrick Soon-Shiong
author_sort	Shiho Tanaka
title	An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants
title_short	An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants
title_full	An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants
title_fullStr	An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants
title_full_unstemmed	An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants
title_sort	ace2 triple decoy that neutralizes sars-cov-2 shows enhanced affinity for virus variants
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4c4a182a1df54a5cb62090f68bebf693
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An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants

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