Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

eLife

Janine Niederhöfer¹  Gerald Wirnsberger¹  Esther Föderl-Höbenreich²  Kurt Zatloukal²  Josef M Penninger³  Chris Oostenbrink⁴  Tümay Capraz⁴  Jan W Perthold⁴  Daniel Maresch⁵  Clemens Grünwald-Gruber⁵  Johannes Stadlmann⁶  Elisabeth Laurent⁷  Lukas Mach⁸  Nikolaus F Kienzl⁸  Vanessa Monteil⁹  Ali Mirazimi^1,10 

[1] Apeiron Biologics, Vienna, Austria;Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria;IMBA - 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, Canada;Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria;Institute of Biochemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria;Institute 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, Austria;Institute of Molecular Biotechnology, Department of Biotechnology and Core Facility Biomolecular & Cellular Analysis, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria;Institute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria;Karolinska Institute, Department of Laboratory Medicine, Stockholm, Sweden;Karolinska Institute, Department of Laboratory Medicine, Stockholm, Sweden;National Veterinary Institute, Uppsala, Sweden;

关键词: SARS-CoV-2;    angiotensin converting enzyme 2;    ACE2;    glycosylation;    Human;    Viruses;   

DOI  :  10.7554/eLife.73641

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY