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.
【저자키워드】 Microbiology, structural biology, Cryoelectron microscopy, 【초록키워드】 neutralizing antibody, Structure, antibodies, SARS-CoV-2, Vaccine, coronavirus, Antiviral, SARS-CoV, VoC, neutralization, variant, variants of concern, virus, COVID-19 therapeutics, Spike protein, Receptor binding domain, Neutralizing activity, nanobody, neutralizing epitope, RBD, comparison, Microscopy, VOCs, target, Neutralizing, mechanisms, epitope, cryo-EM structures, binding, SARS-CoV-2 spike, Analysis, acute respiratory syndrome, host receptor, class, circulating variants, effective, neutralize, bind, STABLE, conserved, eight, provided, indicate, determine, unique, recognize, variety, reveal, disrupt, ACE2-binding site, binding epitope, inaccessible, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, nanobody, Neutralizing, epitope, potent, conserved, circulating variant,