Institute of Plant Biotechnology and Cell Biology, Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences (BOKU), 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
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 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
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.
