Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor
Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-12-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/73641 |
| _version_ | 1828195565384499200 |
|---|---|
| author | Tümay Capraz Nikolaus F Kienzl Elisabeth Laurent Jan W Perthold Esther Föderl-Höbenreich Clemens Grünwald-Gruber Daniel Maresch Vanessa Monteil Janine Niederhöfer Gerald Wirnsberger Ali Mirazimi Kurt Zatloukal Lukas Mach Josef M Penninger Chris Oostenbrink Johannes Stadlmann |
| author_facet | Tümay Capraz Nikolaus F Kienzl Elisabeth Laurent Jan W Perthold Esther Föderl-Höbenreich Clemens Grünwald-Gruber Daniel Maresch Vanessa Monteil Janine Niederhöfer Gerald Wirnsberger Ali Mirazimi Kurt Zatloukal Lukas Mach Josef M Penninger Chris Oostenbrink Johannes Stadlmann |
| author_sort | Tümay Capraz |
| collection | DOAJ |
| description | Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineering of ACE2 N-glycosylation by site-directed mutagenesis or glycosidase treatment resulted in enhanced binding affinities and improved virus neutralization without notable deleterious effects on the structural stability and catalytic activity of the protein. Importantly, simultaneous removal of all accessible N-glycans from recombinant soluble human ACE2 yields a superior SARS-CoV-2 decoy receptor with promise as effective treatment for COVID-19 patients. |
| first_indexed | 2024-04-12T09:45:54Z |
| format | Article |
| id | doaj.art-dbd89a04e5aa482e90ecfe601f9c8ab1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:45:54Z |
| publishDate | 2021-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-dbd89a04e5aa482e90ecfe601f9c8ab12022-12-22T03:37:58ZengeLife Sciences Publications LtdeLife2050-084X2021-12-011010.7554/eLife.73641Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptorTümay Capraz0https://orcid.org/0000-0002-2547-067XNikolaus F Kienzl1https://orcid.org/0000-0001-8057-3930Elisabeth Laurent2https://orcid.org/0000-0002-5234-5524Jan W Perthold3https://orcid.org/0000-0002-8575-0278Esther Föderl-Höbenreich4https://orcid.org/0000-0003-2066-1036Clemens Grünwald-Gruber5https://orcid.org/0000-0002-6097-8348Daniel Maresch6Vanessa Monteil7https://orcid.org/0000-0002-2652-5695Janine Niederhöfer8Gerald Wirnsberger9https://orcid.org/0000-0001-7035-7038Ali Mirazimi10Kurt Zatloukal11https://orcid.org/0000-0001-5299-7218Lukas Mach12https://orcid.org/0000-0001-9013-5408Josef M Penninger13https://orcid.org/0000-0002-8194-3777Chris Oostenbrink14https://orcid.org/0000-0002-4232-2556Johannes Stadlmann15https://orcid.org/0000-0001-5693-6690Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, AustriaInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences (BOKU), Vienna, AustriaInstitute of Molecular Biotechnology, Department of Biotechnology and Core Facility Biomolecular & Cellular Analysis, University of Natural Resources and Life Sciences (BOKU), Vienna, AustriaInstitute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, AustriaDiagnostic and Research Institute of Pathology, Medical University of Graz, Graz, AustriaInstitute of Biochemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, AustriaInstitute of Biochemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, AustriaKarolinska Institute, Department of Laboratory Medicine, Stockholm, SwedenApeiron Biologics, Vienna, AustriaApeiron Biologics, Vienna, AustriaKarolinska Institute, Department of Laboratory Medicine, Stockholm, Sweden; National Veterinary Institute, Uppsala, SwedenDiagnostic and Research Institute of Pathology, Medical University of Graz, Graz, AustriaInstitute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences (BOKU), Vienna, AustriaIMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr, Vienna, Austria; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, CanadaInstitute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, AustriaInstitute of Biochemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria; IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr, Vienna, AustriaInfection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineering of ACE2 N-glycosylation by site-directed mutagenesis or glycosidase treatment resulted in enhanced binding affinities and improved virus neutralization without notable deleterious effects on the structural stability and catalytic activity of the protein. Importantly, simultaneous removal of all accessible N-glycans from recombinant soluble human ACE2 yields a superior SARS-CoV-2 decoy receptor with promise as effective treatment for COVID-19 patients.https://elifesciences.org/articles/73641SARS-CoV-2angiotensin converting enzyme 2ACE2glycosylation |
| spellingShingle | Tümay Capraz Nikolaus F Kienzl Elisabeth Laurent Jan W Perthold Esther Föderl-Höbenreich Clemens Grünwald-Gruber Daniel Maresch Vanessa Monteil Janine Niederhöfer Gerald Wirnsberger Ali Mirazimi Kurt Zatloukal Lukas Mach Josef M Penninger Chris Oostenbrink Johannes Stadlmann Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor eLife SARS-CoV-2 angiotensin converting enzyme 2 ACE2 glycosylation |
| title | Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor |
| title_full | Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor |
| title_fullStr | Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor |
| title_full_unstemmed | Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor |
| title_short | Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor |
| title_sort | structure guided glyco engineering of ace2 for improved potency as soluble sars cov 2 decoy receptor |
| topic | SARS-CoV-2 angiotensin converting enzyme 2 ACE2 glycosylation |
| url | https://elifesciences.org/articles/73641 |
| work_keys_str_mv | AT tumaycapraz structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT nikolausfkienzl structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT elisabethlaurent structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT janwperthold structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT estherfoderlhobenreich structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT clemensgrunwaldgruber structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT danielmaresch structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT vanessamonteil structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT janineniederhofer structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT geraldwirnsberger structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT alimirazimi structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT kurtzatloukal structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT lukasmach structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT josefmpenninger structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT chrisoostenbrink structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor AT johannesstadlmann structureguidedglycoengineeringoface2forimprovedpotencyassolublesarscov2decoyreceptor |