Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting diverse and conserved epitopes

Dapeng Sun, Zhe Sang, Yong Joon Kim, Yufei Xiang, Tomer Cohen, Anna K. Belford, Alexis Huet, James F. Conway, Ji Sun, Derek J. Taylor, Dina Schneidman-Duhovny (), Cheng Zhang (), Wei Huang () and Yi Shi ()
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Dapeng Sun: University of Pittsburgh
Zhe Sang: The University of Pittsburgh and Carnegie Mellon University Program for Computational Biology
Yong Joon Kim: University of Pittsburgh
Yufei Xiang: University of Pittsburgh
Tomer Cohen: The Hebrew University of 6
Anna K. Belford: University of Pittsburgh
Alexis Huet: University of Pittsburgh
James F. Conway: University of Pittsburgh
Ji Sun: St. Jude Children’s Research Hospital
Derek J. Taylor: Case Western Reserve University
Dina Schneidman-Duhovny: The Hebrew University of 6
Cheng Zhang: University of Pittsburgh
Wei Huang: Case Western Reserve University
Yi Shi: The University of Pittsburgh and Carnegie Mellon University Program for Computational Biology

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Interventions against variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Stable and potent nanobodies (Nbs) that target the receptor binding domain (RBD) of SARS-CoV-2 spike are promising therapeutics. However, it is unknown if Nbs broadly neutralize circulating variants. We found that RBD Nbs are highly resistant to variants of concern (VOCs). High-resolution cryoelectron microscopy determination of eight Nb-bound structures reveals multiple potent neutralizing epitopes clustered into three classes: Class I targets ACE2-binding sites and disrupts host receptor binding. Class II binds highly conserved epitopes and retains activity against VOCs and RBDSARS-CoV. Cass III recognizes unique epitopes that are likely inaccessible to antibodies. Systematic comparisons of neutralizing antibodies and Nbs provided insights into how Nbs target the spike to achieve high-affinity and broadly neutralizing activity. Structure-function analysis of Nbs indicates a variety of antiviral mechanisms. Our study may guide the rational design of pan-coronavirus vaccines and therapeutics.

Date: 2021
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DOI: 10.1038/s41467-021-24963-3

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