Journal
ANTIVIRAL RESEARCH
Volume 205, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.antiviral.2022.105383
Keywords
COVID-19; SARS-CoV-2; sACE2; Adeno-associated virus (AAV) vector; Variants
Categories
Funding
- National Key R&D Program of China [2021YFC2300103, 2022YFE0203100]
- National Natural Science Foundation of China [82041043]
- Natural Science Foundation of Guangdong Province [2019A1515110458]
- China Postdoctoral Science Foundation [2020T130150ZX]
- Shenzhen Science and Technology Program [20190804095916056, JSGG20200225152008136, GXWD2 0201231165807008, 20200825113322001, RCJC202107060920090 04]
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The emergence of SARS-CoV-2 variants has reduced the effectiveness of existing vaccines and antibody therapy against COVID-19. However, the use of soluble human ACE2 (shACE2) or dog ACE2 (dACE2(24-83)) as decoys can effectively block the infections of SARS-CoV-2 variants. This study highlights a promising therapeutic strategy.
The frequently emerging SARS-CoV-2 variants have weakened the effectiveness of existing COVID-19 vaccines and neutralizing antibody therapy. Nevertheless, the infections of SARS-CoV-2 variants still depend on angiotensin-converting enzyme 2 (ACE2) receptor-mediated cell entry, and thus the soluble human ACE2 (shACE2) is a potential decoy for broadly blocking SARS-CoV-2 variants. In this study, we firstly generated the recombinant AAVrh10-vectored shACE2 constructs, a kind of adeno-associated virus (AAV) serotype with pulmonary tissue tropism, and then validated its inhibition capacity against SARS-CoV-2 infection. To further optimize the minimized ACE2 functional domain candidates, a comprehensive analysis was performed to clarify the interactions between the ACE2 orthologs from various species and the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein. Based on the key interface amino acids, we designed a series of truncated ACE2 orthologs, and then assessed their potential affinity to bind to SARS-CoV-2 variants RBD in silico. Of note, we found that the 24-83aa fragment of dog ACE2 (dACE2(24-83)) had a higher affinity to the RBD of SARS-CoV-2 variants than that of human ACE2. Importantly, AAVrh10-vectored shACE2 or dACE2(24-83) constructs exhibited a broadly blockage breadth against SARS-CoV-2 prototype and variants in vitro and ex vivo. Collectively, these data highlighted a promising therapeutic strategy against SARS-CoV-2 variants.
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