| Literature DB >> 33893175 |
Phillip Pymm1,2, Amy Adair1, Li-Jin Chan1,2, James P Cooney1,2, Francesca L Mordant3, Cody C Allison1,2, Ester Lopez3, Ebene R Haycroft3, Matthew T O'Neill1, Li Lynn Tan1, Melanie H Dietrich1,2, Damien Drew1, Marcel Doerflinger1,2, Michael A Dengler1,2, Nichollas E Scott3, Adam K Wheatley3,4, Nicholas A Gherardin3,5, Hariprasad Venugopal6, Deborah Cromer7,8, Miles P Davenport7, Raelene Pickering9, Dale I Godfrey3,5, Damian F J Purcell3, Stephen J Kent3,4, Amy W Chung3, Kanta Subbarao3,10, Marc Pellegrini1,2, Alisa Glukhova1,11,12, Wai-Hong Tham13,2.
Abstract
Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.Entities:
Keywords: SARS-CoV-2; antiviral therapeutics; cryo-EM; crystallography; nanobodies
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Year: 2021 PMID： 33893175 DOI： 10.1073/pnas.2101918118
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205