TY - JOUR T1 - Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting novel and conserved epitopes JF - bioRxiv DO - 10.1101/2021.03.09.434592 SP - 2021.03.09.434592 AU - Dapeng Sun AU - Zhe Sang AU - Yong Joon Kim AU - Yufei Xiang AU - Tomer Cohen AU - Anna K. Belford AU - Alexis Huet AU - James F. Conway AU - Ji Sun AU - Derek J. Taylor AU - Dina Schneidman-Duhovny AU - Cheng Zhang AU - Wei Huang AU - Yi Shi Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/10/2021.03.09.434592.abstract N2 - There is an urgent need to develop effective interventions resistant to the evolving variants of SARS-CoV-2. Nanobodies (Nbs) are stable and cost-effective agents that can be delivered by novel aerosolization route to treat SARS-CoV-2 infections efficiently. However, it remains unknown if they possess broadly neutralizing activities against the prevalent circulating strains. We found that potent neutralizing Nbs are highly resistant to the convergent variants of concern that evade a large panel of neutralizing antibodies (Abs) and significantly reduce the activities of convalescent or vaccine-elicited sera. Subsequent determination of 9 high-resolution structures involving 6 potent neutralizing Nbs by cryoelectron microscopy reveals conserved and novel epitopes on virus spike inaccessible to Abs. Systematic structural comparison of neutralizing Abs and Nbs provides critical insights into how Nbs uniquely target the spike to achieve high-affinity and broadly neutralizing activity against the evolving virus. Our study will inform the rational design of novel pan-coronavirus vaccines and therapeutics.Competing Interest StatementUniversity of Pittsburgh has filed a patent application related to the nanobodies of this study ER -