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Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike #MMPMID32585135
Huo J; Zhao Y; Ren J; Zhou D; Duyvesteyn HME; Ginn HM; Carrique L; Malinauskas T; Ruza RR; Shah PNM; Tan TK; Rijal P; Coombes N; Bewley KR; Tree JA; Radecke J; Paterson NG; Supasa P; Mongkolsapaya J; Screaton GR; Carroll M; Townsend A; Fry EE; Owens RJ; Stuart DI
Cell Host Microbe 2020[Sep]; 28 (3): 445-454.e6 PMID32585135show ga
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 A 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.
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Cell+Host+Microbe 2020 ; 28 (3): 445-454.e6
