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A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19
- Source :
- Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021), Nature Communications
- Publication Year :
- 2021
- Publisher :
- Nature Portfolio, 2021.
-
Abstract
- SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.<br />Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.
- Subjects :
- Male
medicine.medical_treatment
Science
Mutant
Intraperitoneal injection
Dose-Response Relationship, Immunologic
General Physics and Astronomy
Hamster
Alpha (ethology)
Crystallography, X-Ray
Article
General Biochemistry, Genetics and Molecular Biology
Epitope
Epitopes
Neutralization Tests
medicine
Antibody fragment therapy
Animals
Administration, Intranasal
X-ray crystallography
Multidisciplinary
Mesocricetus
biology
SARS-CoV-2
Chemistry
Cryoelectron Microscopy
General Chemistry
Single-Domain Antibodies
biology.organism_classification
Antibodies, Neutralizing
Virology
COVID-19 Drug Treatment
Disease Models, Animal
Spike Glycoprotein, Coronavirus
biology.protein
Female
Antibody
Golden hamster
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 12
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....88bfe2f67b6c2ee50cd8f27682defac4