Rational design of AAVrh10-vectored ACE2 functional domain to broadly block the cell entry of SARS-CoV-2 variants
Brief intro:
- Author: Minchao Li, Jiaoshan Chen, Yajie Liu, Jin Zhao, Yanjun Li, Yunqi Hu, Yao-qing Chen, Litao Sun, Yuelong Shu, Fengling Feng, and Caijun Sun
- Journal: Antiviral Research
- Doi: https://www.doi.org/10.1016/j.antiviral.2022.105383
- Publication Date: 2022 Jul 30
Products/Services used in the paper
Quotation shows PackGene:AAVrh10 expressing the different ACE2 fragments, including shACE2, shACE2PD, shACE2(PD + Neck), hACE224-83, dACE224-83, were packaged by PackGene Biotech.
Research Field:Covid-related
AAV Serotype:AAVrh10
Animal or cell line strain:6-8-week-old female BALB/c mice
Abstract
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 (dACE224-83) had a higher affinity to the RBD of SARS-CoV-2 variants than that of human ACE2. Importantly, AAVrh10-vectored shACE2 or dACE224-83 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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