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

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Nat Commun


. 2021 Aug 3;12(1):4676.
doi: 10.1038/s41467-021-24963-3.
Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting diverse and conserved epitopes


Dapeng Sun ^{# 1} , Zhe Sang ^{# 2 3} , Yong Joon Kim ^{# 3 4} , Yufei Xiang ^{# 3} , Tomer Cohen ⁵ , Anna K Belford ⁶ , Alexis Huet ⁶ , James F Conway ⁶ , Ji Sun ⁷ , Derek J Taylor ^{8 9} , Dina Schneidman-Duhovny ¹⁰ , Cheng Zhang ¹¹ , Wei Huang ¹² , Yi Shi ^{13 14 15}



Affiliations

• PMID: 34344900
• DOI: 10.1038/s41467-021-24963-3

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 RBD_SARS-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.