Generation of enzymatically competent SARS‐CoV‐2 decoy receptor ACE2‐Fc in glycoengineered Nicotiana benthamiana

Human angiotensin‐converting enzyme 2 (ACE2) is the primary host cell receptor for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binding and cell entry. Administration of high concentrations of soluble ACE2 can be utilized as a decoy to block the interaction of the virus with cellular ACE2 receptors and potentially be used as a strategy for treatment or prevention of coronavirus disease 2019. Human ACE2 is heavily glycosylated and its glycans impact on binding to the SARS‐CoV‐2 spike protein and virus infectivity. Here, we describe the production of a recombinant soluble ACE2‐fragment crystallizable (Fc) variant in glycoengineered Nicotiana benthamiana. Our data reveal that the produced dimeric ACE2‐Fc variant is glycosylated with mainly complex human‐type N‐glycans and functional with regard to enzyme activity, affinity to the SARS‐CoV‐2 receptor‐binding domain, and wild‐type virus neutralization. Human angiotensin‐converting enzyme 2 (ACE2) is the primary receptor for SARS‐CoV‐2 cell entry and recombinant ACE2 variants have great therapeutic potential to treat or prevent COVID‐19. Here, we show that a glycosylated recombinant ACE2‐Fc fusion protein can be produced in glycoengineered Nicotiana benthamiana with favorable glycosylation.