Journal Article

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

Shi, Yi, Sun, Dapeng, Belford, Anna K., Zhang, Cheng, Huet, Alexis, Kim, Yong Joon, Xiang, Yufei, Taylor, Derek J., Sun, Ji, Sang, Zhe, Conway, James F., Huang, Wei, Cohen, Tomer, Schneidman-Duhovny, Dina

2021

Overview

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. Highly potent neutralizing nanobodies (Nbs) are of great interest as potential COVID-19 therapeutics. Here, the authors show that potent neutralizing Nbs targeting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein are also effective against convergent variants of concern of the virus. They determine eight Nb-bound spike protein cryo-EM structures, classify the binding epitopes of the Nbs and discuss their neutralization mechanisms.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 101/28 / 631/326 / 631/45/535/1258/1259 / 631/535 / ACE2 / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - chemistry / Angiotensin-Converting Enzyme 2 - metabolism / Antibodies / Antibodies, Monoclonal - chemistry / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - metabolism / Antiviral drugs / Binding Sites / Broadly Neutralizing Antibodies - chemistry / Broadly Neutralizing Antibodies - classification / Broadly Neutralizing Antibodies - immunology / Broadly Neutralizing Antibodies - metabolism / Convergence / Coronaviruses / COVID-19 / COVID-19 - prevention & control / COVID-19 Drug Treatment / Domains / Epitopes / Epitopes - chemistry / Epitopes - immunology / Epitopes - metabolism / Function analysis / Humanities and Social Sciences / Humans / Models, Molecular / multidisciplinary / Mutation / Nanobodies / Neutralization / Neutralizing / Protein Binding / Proteins / Receptors / SARS-CoV-2 - genetics / SARS-CoV-2 - immunology / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Single-Domain Antibodies - chemistry / Single-Domain Antibodies - classification / Single-Domain Antibodies - immunology / Single-Domain Antibodies - metabolism / Spike Glycoprotein, Coronavirus - chemistry / Spike Glycoprotein, Coronavirus - genetics / Spike Glycoprotein, Coronavirus - immunology / Spike Glycoprotein, Coronavirus - metabolism / Spike protein / Structure-Activity Relationship / Structure-function relationships / Viral diseases