A super-potent tetramerized ACE2 protein displays enhanced neutralization of SARS-CoV-2 virus infection

DOI: 10.1038/s41598-021-89957-z

Authors: Ami Miller (Institute of Cancer Research) , Adam Leach (Institute of Cancer Research) , Jemima Thomas (Institute of Cancer Research) , Craig Mcandrew (Institute of Cancer Research) , Emma Bentley (National Institute for Biological Standards and Control) , Giada Mattiuzzo (National Institute for Biological Standards and Control) , Lijo John (National Veterinary Institute (SVA)) , Ali Mirazimi (National Veterinary Institute (SVA); Karolinska Institute) , Gemma Harris (Research Complex at Harwell, Diamond Light Source) , Nadisha Gamage (Diamond Light Source) , Stephen Carr (Research Complex at Harwell) , Hanif Ali (Quadrucept Limited) , Rob Van Montfort (Institute of Cancer Research) , Terence Rabbitts (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 11

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 27159

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.

Journal Keywords: Drug discovery; Immunology

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: Membrane Protein Laboratory (MPL)
Instruments: B21-High Throughput SAXS

Added On: 24/05/2021 14:30

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)