Abstract
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.
Highlights
The rapid spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative pathogen of human coronavirus disease 2019 (COVID-19), has resulted in an unprecedented pandemic and worldwide health crisis
Conformation were shown to bind to two separate human ACE2 (hACE2) molecules,[31] we decided to study the effect of the glycans on the Spike hACE2 interaction using the model with a single receptor binding domain (RBD) in the “up conformation
This provided information on the glycans attached to N690, a glycosylation site not covered in previous glycoproteomic studies of soluble hACE2.21,30 For recombinant trimeric Spike the glyco-analysis has been reported elsewhere.[10,20,21,32]
Summary
The rapid spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative pathogen of human coronavirus disease 2019 (COVID-19), has resulted in an unprecedented pandemic and worldwide health crisis. CoV and Middle Eastern Respiratory Syndrome (MERS)-CoV, SARS-CoV-2 is highly transmissible and can lead to lethal pneumonia and multi-organ failure.[1] For infection and viral entry, the Spike surface protein of SARS-CoV-2 binds to angiotensin converting enzyme 2. Spike,[4] can effectively neutralize SARS-CoV-2 infections,[5,6] and the corresponding drug candidate APN01 has undergone a phase 2 clinical trial for the treatment of hospitalized cases of COVID-19 (ClinicalTrials.gov Identifier: NCT04335136). A first case study of its use in a patient has been reported recently.[7] an aerosol formulation of APN01 has been developed and is currently undergoing Phase I clinical studies
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