Abstract
Approaches are needed for therapy of the severe acute respiratory syndrome from SARS-CoV-2 coronavirus (COVID-19). Interfering with the interaction of viral antigens with the angiotensin converting enzyme 2 (ACE-2) receptor is a promising strategy by blocking the infection of the coronaviruses into human cells. We have implemented a novel protein engineering technology to produce a super-potent tetravalent form of ACE2, coupled to the human immunoglobulin γ1 Fc region, using a self-assembling, tetramerization domain from p53 protein. This high molecular weight Quad protein (ACE2-Fc-TD) retains binding to the SARS-CoV-2 receptor binding spike protein and can form a complex with the spike protein plus anti-viral antibodies. The ACE2-Fc-TD acts as a powerful decoy protein that out-performs soluble monomeric and dimeric ACE2 proteins and blocks both SARS-CoV-2 pseudovirus and SARS-CoV-2 virus infection with greatly enhanced efficacy. The ACE2 tetrameric protein complex promise to be important for development as decoy therapeutic proteins against COVID-19. In contrast to monoclonal antibodies, ACE2 decoy is unlikely to be affected by mutations in SARS-CoV-2 that are beginning to appear in variant forms. In addition, ACE2 multimeric proteins will be available as therapeutic proteins should new coronaviruses appear in the future because these are likely to interact with ACE2 receptor.
Highlights
Approaches are needed for therapy of the severe acute respiratory syndrome from SARS-CoV-2 coronavirus (COVID-19)
Therapeutic approaches to COVID-19 largely depend on preventing the SARS-CoV-2 coronavirus from infecting epithelial cells in airways such as in development of vaccines[4,5] and potentially antibodies[6,7]
Our results show that tetrameric ACE2 could efficiently inhibit SARSCoV-2 attachment to the cells, thereby reducing infection, and that valency of the ACE2 protein is a key determinant of increased potency
Summary
Approaches are needed for therapy of the severe acute respiratory syndrome from SARS-CoV-2 coronavirus (COVID-19). Therapeutic approaches to COVID-19 largely depend on preventing the SARS-CoV-2 coronavirus from infecting epithelial cells in airways such as in development of vaccines[4,5] and potentially antibodies[6,7] These can interact with the virus spike coat proteins to either cause T cell-based immunity or interference with viral binding to the ACE2 cell receptor for internalisation. We have developed and characterised a new potent form of ACE2 protein which comprises four ACE2 extracellular domains by implementing a new technology that generates tetrameric proteins, termed Quads[11] This Quad protein binds the SARS-CoV-2 spike protein receptor binding domain (RBD) with high avidity and interferes with virus infection to a greater extent than other available recombinant ACE2 proteins, producing a super-potent molecule suitable for development for therapeutic use. A ChemiDoc Imaging system (BioRad) was used to capture images
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