Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

By J. Huo, Yuguang Zhao, Jingshan Ren, Daming Zhou, Helen M. E. Duyvesteyn, H. Ginn, L. Carrique, Tomas Malinauskas, R. Ruza, P. Shah and 15 more. 2020

74 citations recorded by the source corpus.

Summary There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

Subfields: Animal Science and Zoology, Infectious Diseases

Citations in the corpus

• Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “CR3022 is a weakly neutralizing Ab that binds to a conserved, cryptic epitope in the RBD (site II) that becomes accessible upon opening of two neighboring RBDs but is distinct from the RBM (site I), the surface of the RBD that interacts with ACE2 (Huo et al., 2020; Piccoli et al., 2020; ter Meulen e”