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Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy

Angiotensin converting enzyme 2 (ACE2) is a key receptor present on cell surfaces that directly interacts with the viral spike (S) protein of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). It is proposed that inhibiting this interaction can be promising in treating COVID‐19. Here,...

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Autores principales: Xie, Feng, Su, Peng, Pan, Ting, Zhou, Xiaoxue, Li, Heyu, Huang, Huizhe, Wang, Aijun, Wang, Fangwei, Huang, Jun, Yan, Haiyan, Zeng, Linghui, Zhang, Long, Zhou, Fangfang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646473/
https://www.ncbi.nlm.nih.gov/pubmed/34665481
http://dx.doi.org/10.1002/adma.202103471
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author Xie, Feng
Su, Peng
Pan, Ting
Zhou, Xiaoxue
Li, Heyu
Huang, Huizhe
Wang, Aijun
Wang, Fangwei
Huang, Jun
Yan, Haiyan
Zeng, Linghui
Zhang, Long
Zhou, Fangfang
author_facet Xie, Feng
Su, Peng
Pan, Ting
Zhou, Xiaoxue
Li, Heyu
Huang, Huizhe
Wang, Aijun
Wang, Fangwei
Huang, Jun
Yan, Haiyan
Zeng, Linghui
Zhang, Long
Zhou, Fangfang
author_sort Xie, Feng
collection PubMed
description Angiotensin converting enzyme 2 (ACE2) is a key receptor present on cell surfaces that directly interacts with the viral spike (S) protein of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). It is proposed that inhibiting this interaction can be promising in treating COVID‐19. Here, the presence of ACE2 in extracellular vesicles (EVs) is reported and the EV‐ACE2 levels are determined by protein palmitoylation. The Cys141 and Cys498 residues on ACE2 are S‐palmitoylated by zinc finger DHHC‐Type Palmitoyltransferase 3 (ZDHHC3) and de‐palmitoylated by acyl protein thioesterase 1 (LYPLA1), which is critical for the membrane‐targeting of ACE2 and their EV secretion. Importantly, by fusing the S‐palmitoylation‐dependent plasma membrane (PM) targeting sequence with ACE2, EVs enriched with ACE2 on their surface (referred to as PM‐ACE2‐EVs) are engineered. It is shown that PM‐ACE2‐EVs can bind to the SARS‐CoV‐2 S‐RBD with high affinity and block its interaction with cell surface ACE2 in vitro. PM‐ACE2‐EVs show neutralization potency against pseudotyped and authentic SARS‐CoV‐2 in human ACE2 (hACE2) transgenic mice, efficiently block viral load of authentic SARS‐CoV‐2, and thus protect host against SARS‐CoV‐2‐induced lung inflammation. The study provides an efficient engineering protocol for constructing a promising, novel biomaterial for application in prophylactic and therapeutic treatments against COVID‐19.
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spelling pubmed-86464732021-12-06 Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy Xie, Feng Su, Peng Pan, Ting Zhou, Xiaoxue Li, Heyu Huang, Huizhe Wang, Aijun Wang, Fangwei Huang, Jun Yan, Haiyan Zeng, Linghui Zhang, Long Zhou, Fangfang Adv Mater Research Articles Angiotensin converting enzyme 2 (ACE2) is a key receptor present on cell surfaces that directly interacts with the viral spike (S) protein of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). It is proposed that inhibiting this interaction can be promising in treating COVID‐19. Here, the presence of ACE2 in extracellular vesicles (EVs) is reported and the EV‐ACE2 levels are determined by protein palmitoylation. The Cys141 and Cys498 residues on ACE2 are S‐palmitoylated by zinc finger DHHC‐Type Palmitoyltransferase 3 (ZDHHC3) and de‐palmitoylated by acyl protein thioesterase 1 (LYPLA1), which is critical for the membrane‐targeting of ACE2 and their EV secretion. Importantly, by fusing the S‐palmitoylation‐dependent plasma membrane (PM) targeting sequence with ACE2, EVs enriched with ACE2 on their surface (referred to as PM‐ACE2‐EVs) are engineered. It is shown that PM‐ACE2‐EVs can bind to the SARS‐CoV‐2 S‐RBD with high affinity and block its interaction with cell surface ACE2 in vitro. PM‐ACE2‐EVs show neutralization potency against pseudotyped and authentic SARS‐CoV‐2 in human ACE2 (hACE2) transgenic mice, efficiently block viral load of authentic SARS‐CoV‐2, and thus protect host against SARS‐CoV‐2‐induced lung inflammation. The study provides an efficient engineering protocol for constructing a promising, novel biomaterial for application in prophylactic and therapeutic treatments against COVID‐19. John Wiley and Sons Inc. 2021-10-19 2021-12-09 /pmc/articles/PMC8646473/ /pubmed/34665481 http://dx.doi.org/10.1002/adma.202103471 Text en © 2021 The Authors. Advanced Materials published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Xie, Feng
Su, Peng
Pan, Ting
Zhou, Xiaoxue
Li, Heyu
Huang, Huizhe
Wang, Aijun
Wang, Fangwei
Huang, Jun
Yan, Haiyan
Zeng, Linghui
Zhang, Long
Zhou, Fangfang
Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy
title Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy
title_full Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy
title_fullStr Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy
title_full_unstemmed Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy
title_short Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID‐19 Therapy
title_sort engineering extracellular vesicles enriched with palmitoylated ace2 as covid‐19 therapy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646473/
https://www.ncbi.nlm.nih.gov/pubmed/34665481
http://dx.doi.org/10.1002/adma.202103471
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