The current COVID-19 pandemic, caused by SARS-CoV-2, poses a serious public health threat. Effective therapeutic and prophylactic treatments are urgently needed. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, which binds to the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Here, we developed recombinant human ACE2-Fc fusion protein (hACE2-Fc) and a hACE2-Fc mutant with reduced catalytic activity. hACE2-Fc and the hACE2-Fc mutant both efficiently blocked entry of SARS-CoV-2, SARS-CoV, and HCoV-NL63 into hACE2-expressing cells and inhibited SARS-CoV-2 S protein-mediated cell–cell fusion. hACE2-Fc also neutralized various SARS-CoV-2 strains with enhanced infectivity including D614G and V367F mutations, as well as the emerging SARS-CoV-2 variants, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.1 (Kappa), and B.1.617.2 (Delta), demonstrating its potent and broad-spectrum antiviral effects. In addition, hACE2-Fc proteins protected HBE from SARS-CoV-2 infection. Unlike RBD-targeting neutralizing antibodies, hACE2-Fc treatment did not induce the development of escape mutants. Furthermore, both prophylactic and therapeutic hACE2-Fc treatments effectively protected mice from SARS-CoV-2 infection, as determined by reduced viral replication, weight loss, histological changes, and inflammation in the lungs. The protection provided by hACE2 showed obvious dose-dependent efficacy in vivo. Pharmacokinetic data indicated that hACE2-Fc has a relative long half-life in vivo compared to soluble ACE2, which makes it an excellent candidate for prophylaxis and therapy for COVID-19 as well as for SARS-CoV and HCoV-NL63 infections.
【저자키워드】 immunology, Mechanisms of disease, 【초록키워드】 Treatment, SARS-CoV-2, Inflammation, ACE2, Neutralizing antibodies, SARS-CoV, B.1.351, SARS-COV-2 infection, COVID-19 pandemic, mutations, Delta, B.1.617.2, antiviral effects, Prophylactic, hACE2, Receptor binding domain, Prophylaxis, Protein, infections, SARS-CoV-2 variants, B.1.1.7, mice, RBD, viral replication, B.1.617.1, Lungs, SARS-CoV-2 spike protein, therapeutic, D614G, Beta, mutant, receptor, fusion protein, in vivo, ACE2-Fc, escape mutants, HCoV-NL63, soluble ACE2, weight loss, enzyme, dose-dependent efficacy, SARS-CoV-2 S, SARS-CoV-2 strain, prophylactic treatment, catalytic activity, public health threat, neutralized, V367F, bind, histological changes, blocked, caused, indicated, addition, inhibited, provided, reduced, functional, induce, entry of SARS-CoV-2, hACE2-expressing cell, therapy for COVID-19, 【제목키워드】 SARS-COV-2 infection, Prophylactic, in vivo, ACE2-Fc, potent, therapeutic efficacy,