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TitleStructure-guided design of a trivalent nanobody cluster targeting SARS-CoV-2 spike protein.
Journal, issue, pagesInt J Biol Macromol, Vol. 256, Issue Pt 1, Page 128191, Year 2024
Publish dateNov 22, 2023
AuthorsXinyi Jiang / Qin Qin / Haixia Zhu / Jiaqiang Qian / Qiang Huang /
PubMed AbstractNanobodies are natural anti-SARS-CoV-2 drug candidates. Engineering multivalent nanobodies is an effective way to improve the functional binding affinity of natural nanobodies by simultaneously ...Nanobodies are natural anti-SARS-CoV-2 drug candidates. Engineering multivalent nanobodies is an effective way to improve the functional binding affinity of natural nanobodies by simultaneously targeting multiple sites on viral proteins. However, multivalent nanobodies have usually been engineered by trial and error, and rational designs are still lacking. Here, we describe a structure-guided design of a self-assembled trivalent nanobody cluster targeting the SARS-CoV-2 spike protein. Using the nanobody Nb6 as a monovalent binder, we first selected a human-derived trimerization scaffold evaluated by molecular dynamics simulations, then selected an optimal linker according to the minimum distance between Nb6 and the trimerization scaffold, and finally successfully engineered a trivalent nanobody cluster called Tribody. Compared with the low-affinity monovalent counterpart (Nb6), Tribody showed much higher target binding affinity (K < 1 pM) and thus had a 900-fold increase in antiviral neutralization against SARS-CoV-2 pseudovirus. We determined the cryo-EM structure of the Tribody-spike complex and confirmed that all three Nb6 binders of Tribody collectively bind to the three receptor-binding domains (RBDs) of the spike and lock them in a 3-RBD-down conformation, fully consistent with our structure-guided design. This study demonstrates that synthetic nanobody clusters with human-derived self-assembled scaffolds are potential protein drugs against SARS-CoV-2 coronaviruses.
External linksInt J Biol Macromol / PubMed:38000614
MethodsEM (single particle)
Resolution4.2 Å
Structure data

36904

8w4f

EMDB-36904, PDB-8w4f:
SARS-CoV-2 spike protein in complex with a trivalent nanobody
Method: EM (single particle) / Resolution: 4.2 Å

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / trivalent nanobody / viral neutralization / all-RBD-down spike / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex

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