tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Zhe Sang[SUP] #[/SUP][SUP] 2 3 [/SUP], Yong Joon Kim[SUP] #[/SUP][SUP] 3 4 [/SUP], Yufei Xiang[SUP] #[/SUP][SUP] 3 [/SUP], Tomer Cohen[SUP] 5 [/SUP], Anna K Belford[SUP] 6 [/SUP], Alexis Huet[SUP] 6 [/SUP], James F Conway[SUP] 6 [/SUP], Ji Sun[SUP] 7 [/SUP], Derek J Taylor[SUP] 8 9 [/SUP], Dina Schneidman-Duhovny[SUP] 10 [/SUP], Cheng Zhang[SUP] 11 [/SUP], Wei Huang[SUP] 12 [/SUP], Yi Shi[SUP] 13 14 15 [/SUP]
Affiliations
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[SUB]SARS-CoV[/SUB]. 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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Zhe Sang[SUP] #[/SUP][SUP] 2 3 [/SUP], Yong Joon Kim[SUP] #[/SUP][SUP] 3 4 [/SUP], Yufei Xiang[SUP] #[/SUP][SUP] 3 [/SUP], Tomer Cohen[SUP] 5 [/SUP], Anna K Belford[SUP] 6 [/SUP], Alexis Huet[SUP] 6 [/SUP], James F Conway[SUP] 6 [/SUP], Ji Sun[SUP] 7 [/SUP], Derek J Taylor[SUP] 8 9 [/SUP], Dina Schneidman-Duhovny[SUP] 10 [/SUP], Cheng Zhang[SUP] 11 [/SUP], Wei Huang[SUP] 12 [/SUP], Yi Shi[SUP] 13 14 15 [/SUP]
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[SUB]SARS-CoV[/SUB]. 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.