期刊
CELL DISCOVERY
卷 7, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41421-021-00302-0
关键词
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类别
资金
- National Key R&D Program of China [2018YFC1200100, 2018ZX10301403, 2018YFC1311900, 2020YFC0842400]
- National Natural Science Foundation of China [82025001]
- Ministry of Science and Technology of Guangdong province [2020B1111330001, 2020A111128008, 2020B1111320003, 2020A0505100063, 2020KZDZX1158, B195001248, 2020A1515010911, 2019TX05Y120]
- Guangdong Science and Technology Foundation [2019B030316028]
- Guangzhou Institute of Respiratory Health Open Project (China Evergrande Group) [2020GIRHHMS07, 2020GIRHHMS24]
- State Key Laboratory of Respiratory Disease [SKLRD-QN-201912, SKLRD-Z-202007]
- Guangzhou Medical University High-level University Innovation Team Training Program (Guangzhou Medical University) [159]
- Ministry of Education of Guangdong province [2020B1111330001, 2020A111128008, 2020B1111320003, 2020A0505100063, 2020KZDZX1158, B195001248, 2020A1515010911, 2019TX05Y120]
The developed hACE2-Fc fusion protein and mutant show potent antiviral effects against various coronaviruses, including SARS-CoV-2 variants, in cell experiments and mouse models. The drug has a relatively long half-life, making it suitable for prophylaxis and therapy for COVID-19, SARS-CoV, and HCoV-NL63 infections.
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.
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