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

eLife

Johannes Stadlmann¹  Kurt Zatloukal²  Gerald Wirnsberger³  Janine Niederhöfer³  Lukas Mach⁴  Esther Föderl-Höbenreich⁴  Chris Oostenbrink⁵  Tümay Capraz⁶  Jan W Perthold⁶  Daniel Maresch⁷  Clemens Grünwald-Gruber⁷  Elisabeth Laurent⁸  Nikolaus F Kienzl⁹  Josef M Penninger⁹  Vanessa Monteil^1,10  Ali Mirazimi^1,10 

[1] Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada;National Veterinary Institute, Uppsala, Sweden;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;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 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;

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

DOI  :  10.7554/eLife.73641

来源: DOAJ

【 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】

Unknown