Cargando…
Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo
As severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolves to escape natural antibodies, it also loses sensitivity to therapeutic antibody drugs. By contrast, evolution selects for binding to ACE2, the cell-surface receptor required for SARS-CoV-2 infection. Consistent with this, we fin...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728973/ https://www.ncbi.nlm.nih.gov/pubmed/36475798 http://dx.doi.org/10.1126/sciadv.abq6527 |
_version_ | 1784845388490997760 |
---|---|
author | Torchia, James A. Tavares, Alexander H. Carstensen, Laura S. Chen, Da-Yuan Huang, Jessie Xiao, Tianshu Mukherjee, Sonia Reeves, Patrick M. Tu, Hua Sluder, Ann E. Chen, Bing Kotton, Darrell N. Bowen, Richard A. Saeed, Mohsan Poznansky, Mark C. Freeman, Gordon J. |
author_facet | Torchia, James A. Tavares, Alexander H. Carstensen, Laura S. Chen, Da-Yuan Huang, Jessie Xiao, Tianshu Mukherjee, Sonia Reeves, Patrick M. Tu, Hua Sluder, Ann E. Chen, Bing Kotton, Darrell N. Bowen, Richard A. Saeed, Mohsan Poznansky, Mark C. Freeman, Gordon J. |
author_sort | Torchia, James A. |
collection | PubMed |
description | As severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolves to escape natural antibodies, it also loses sensitivity to therapeutic antibody drugs. By contrast, evolution selects for binding to ACE2, the cell-surface receptor required for SARS-CoV-2 infection. Consistent with this, we find that an ACE2 decoy neutralizes antibody-resistant variants, including Omicron, with no loss in potency. To identify design features necessary for in vivo activity, we compare several enzymatically inactive, Fc effector–silenced ACE2-Fc decoys. Inclusion of the ACE2 collectrin-like domain not only improves affinity for the S protein but also unexpectedly extends serum half-life and is necessary to reduce disease severity and viral titer in Syrian hamsters. Fc effector function is not required. The activity of ACE2 decoy receptors is due, in part, to their ability to trigger an irreversible structural change in the viral S protein. Our studies provide a new understanding of how ACE2 decoys function and support their development as therapeutics to treat ACE2-dependent coronaviruses. |
format | Online Article Text |
id | pubmed-9728973 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97289732022-12-13 Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo Torchia, James A. Tavares, Alexander H. Carstensen, Laura S. Chen, Da-Yuan Huang, Jessie Xiao, Tianshu Mukherjee, Sonia Reeves, Patrick M. Tu, Hua Sluder, Ann E. Chen, Bing Kotton, Darrell N. Bowen, Richard A. Saeed, Mohsan Poznansky, Mark C. Freeman, Gordon J. Sci Adv Biomedicine and Life Sciences As severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolves to escape natural antibodies, it also loses sensitivity to therapeutic antibody drugs. By contrast, evolution selects for binding to ACE2, the cell-surface receptor required for SARS-CoV-2 infection. Consistent with this, we find that an ACE2 decoy neutralizes antibody-resistant variants, including Omicron, with no loss in potency. To identify design features necessary for in vivo activity, we compare several enzymatically inactive, Fc effector–silenced ACE2-Fc decoys. Inclusion of the ACE2 collectrin-like domain not only improves affinity for the S protein but also unexpectedly extends serum half-life and is necessary to reduce disease severity and viral titer in Syrian hamsters. Fc effector function is not required. The activity of ACE2 decoy receptors is due, in part, to their ability to trigger an irreversible structural change in the viral S protein. Our studies provide a new understanding of how ACE2 decoys function and support their development as therapeutics to treat ACE2-dependent coronaviruses. American Association for the Advancement of Science 2022-12-07 /pmc/articles/PMC9728973/ /pubmed/36475798 http://dx.doi.org/10.1126/sciadv.abq6527 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Torchia, James A. Tavares, Alexander H. Carstensen, Laura S. Chen, Da-Yuan Huang, Jessie Xiao, Tianshu Mukherjee, Sonia Reeves, Patrick M. Tu, Hua Sluder, Ann E. Chen, Bing Kotton, Darrell N. Bowen, Richard A. Saeed, Mohsan Poznansky, Mark C. Freeman, Gordon J. Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo |
title | Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo |
title_full | Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo |
title_fullStr | Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo |
title_full_unstemmed | Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo |
title_short | Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo |
title_sort | optimized ace2 decoys neutralize antibody-resistant sars-cov-2 variants through functional receptor mimicry and treat infection in vivo |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728973/ https://www.ncbi.nlm.nih.gov/pubmed/36475798 http://dx.doi.org/10.1126/sciadv.abq6527 |
work_keys_str_mv | AT torchiajamesa optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT tavaresalexanderh optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT carstensenlauras optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT chendayuan optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT huangjessie optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT xiaotianshu optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT mukherjeesonia optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT reevespatrickm optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT tuhua optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT sluderanne optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT chenbing optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT kottondarrelln optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT bowenricharda optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT saeedmohsan optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT poznanskymarkc optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo AT freemangordonj optimizedace2decoysneutralizeantibodyresistantsarscov2variantsthroughfunctionalreceptormimicryandtreatinfectioninvivo |