Biparatopic nanobodies targeting the receptor binding domain efficiently neutralise SARS-CoV-2
- Author(s)
- Pymm, P; Redmond, SJ; Dolezal, O; Mordant, F; Lopez, E; Cooney, JP; Davidson, KC; Haycroft, E; Tan, CW; Seneviratna, R; Grimley, SL; Purcell, DFJ; Kent, SJ; Wheatley, AK; Wang, LF; Leis, A; Glukhova, A; Pellegrini, M; Chung, AW; Subbarao, K; Uldrich, AP; Tham, WH; Godfrey, DI; Gherardin, NA;
- Journal Title
- iScience
- Publication Type
- epub ahead of print
- Abstract
- The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralise virus, have potential for treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralise the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralising capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralisers with enhanced ability to control viral escape mutants.
- Publisher
- Elsevier
- Research Division(s)
- Structural Biology; Infectious Diseases And Immune Defence
- PubMed ID
- 36213007
- Publisher's Version
- https://doi.org/10.1016/j.isci.2022.105259
- Open Access at Publisher's Site
https://doi.org/10.1016/j.isci.2022.105259- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-10-14 09:03:11
Last Modified: 2022-10-14 09:08:52