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ACE2 decoy receptor generated by high-throughput saturation mutagenesis efficiently neutralizes SARS-CoV-2 and its prevalent variants.
Wang, Bolun; Zhao, Junxuan; Liu, Shuo; Feng, Jingyuan; Luo, Yufeng; He, Xinyu; Wang, Yanmin; Ge, Feixiang; Wang, Junyi; Ye, Buqing; Huang, Weijin; Bo, Xiaochen; Wang, Youchun; Xi, Jianzhong Jeff.
  • Wang B; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Zhao J; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Liu S; Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, People's Republic of China.
  • Feng J; College of Chemistry, University of California Berkeley, Berkeley, CA, USA.
  • Luo Y; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • He X; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Wang Y; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Ge F; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Wang J; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Ye B; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
  • Huang W; Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, People's Republic of China.
  • Bo X; Institute of Health Service and Transfusion Medicine, Beijing, People's Republic of China.
  • Wang Y; Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, People's Republic of China.
  • Xi JJ; Department of Biomedical Engineering, Peking University, Beijing, People's Republic of China.
Emerg Microbes Infect ; 11(1): 1488-1499, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1852834
ABSTRACT
The recent global pandemic was a spillover from the SARS-CoV-2 virus. Viral entry involves the receptor binding domain (RBD) of the viral spike protein interacting with the protease domain (PD) of the cellular receptor, ACE2. We hereby present a comprehensive mutational landscape of the effects of ACE2-PD point mutations on RBD-ACE2 binding using a saturation mutagenesis approach based on microarray-based oligo synthesis and a single-cell screening assay. We observed that changes in glycosylation sites and directly interacting sites of ACE2-PD significantly influenced ACE2-RBD binding. We further engineered an ACE2 decoy receptor with critical point mutations, D30I, L79W, T92N, N322V, and K475F, named C4-1. C4-1 shows a 200-fold increase in neutralization for the SARS-CoV-2 D614G pseudotyped virus compared to wild-type soluble ACE2 and a sevenfold increase in binding affinity to wild-type spike compared to the C-terminal Ig-Fc fused wild-type soluble ACE2. Moreover, C4-1 efficiently neutralized prevalent variants, especially the omicron variant (EC50=16 ng/mL), and rescued monoclonal antibodies, vaccine, and convalescent sera neutralization from viral immune-escaping. We hope to next investigate translating the therapeutic potential of C4-1 for the treatment of SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Vaccines / Variants Limits: Humans Language: English Journal: Emerg Microbes Infect Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Vaccines / Variants Limits: Humans Language: English Journal: Emerg Microbes Infect Year: 2022 Document Type: Article