tetano
Editor, Senior Moderator
Science
. 2020 Nov 5;eabe3255.
doi: 10.1126/science.abe3255. Online ahead of print.
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Michael Schoof[SUP] #[/SUP][SUP] 1 2 [/SUP], Bryan Faust[SUP] #[/SUP][SUP] 3 2 4 5 [/SUP], Reuben A Saunders[SUP] #[/SUP][SUP] 3 6 [/SUP], Smriti Sangwan[SUP] #[/SUP][SUP] 3 2 [/SUP], Veronica Rezelj[SUP] #[/SUP][SUP] 7 [/SUP], Nick Hoppe[SUP] 4 5 [/SUP], Morgane Boone[SUP] 3 2 [/SUP], Christian B Billesb?lle[SUP] 4 5 [/SUP], Cristina Puchades[SUP] 5 [/SUP], Caleigh M Azumaya[SUP] 5 [/SUP], Huong T Kratochvil[SUP] 5 [/SUP], Marcell Zimanyi[SUP] 3 2 [/SUP], Ishan Deshpande[SUP] 4 5 [/SUP], Jiahao Liang[SUP] 4 [/SUP], Sasha Dickinson[SUP] 5 [/SUP], Henry C Nguyen[SUP] 5 [/SUP], Cynthia M Chio[SUP] 5 [/SUP], Gregory E Merz[SUP] 5 [/SUP], Michael C Thompson[SUP] 5 [/SUP], Devan Diwanji[SUP] 5 [/SUP], Kaitlin Schaefer[SUP] 5 [/SUP], Aditya A Anand[SUP] 3 2 [/SUP], Niv Dobzinski[SUP] 3 2 [/SUP], Beth Shoshana Zha[SUP] 8 [/SUP], Camille R Simoneau[SUP] 9 10 11 [/SUP], Kristoffer Leon[SUP] 9 10 11 [/SUP], Kris M White[SUP] 12 13 [/SUP], Un Seng Chio[SUP] 5 [/SUP], Meghna Gupta[SUP] 5 [/SUP], Mingliang Jin[SUP] 5 [/SUP], Fei Li[SUP] 5 [/SUP], Yanxin Liu[SUP] 5 [/SUP], Kaihua Zhang[SUP] 5 [/SUP], David Bulkley[SUP] 5 [/SUP], Ming Sun[SUP] 5 [/SUP], Amber M Smith[SUP] 5 [/SUP], Alexandrea N Rizo[SUP] 5 [/SUP], Frank Moss[SUP] 5 [/SUP], Axel F Brilot[SUP] 5 [/SUP], Sergei Pourmal[SUP] 5 [/SUP], Raphael Trenker[SUP] 5 [/SUP], Thomas Pospiech[SUP] 5 [/SUP], Sayan Gupta[SUP] 14 [/SUP], Benjamin Barsi-Rhyne[SUP] 4 [/SUP], Vladislav Belyy[SUP] 3 2 [/SUP], Andrew W Barile-Hill[SUP] 15 [/SUP], Silke Nock[SUP] 3 2 [/SUP], Yuwei Liu[SUP] 3 2 [/SUP], Nevan J Krogan[SUP] 5 6 9 10 [/SUP], Corie Y Ralston[SUP] 14 [/SUP], Danielle L Swaney[SUP] 5 6 9 10 [/SUP], Adolfo Garc?a-Sastre[SUP] 12 13 16 17 [/SUP], Melanie Ott[SUP] 9 10 11 [/SUP], Marco Vignuzzi[SUP] 7 [/SUP], QCRG Structural Biology Consortium; Peter Walter[SUP] 1 2 [/SUP], Aashish Manglik[SUP] 18 5 9 19 [/SUP]
Collaborators, Affiliations
Abstract
The SARS-CoV-2 virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
. 2020 Nov 5;eabe3255.
doi: 10.1126/science.abe3255. Online ahead of print.
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Michael Schoof[SUP] #[/SUP][SUP] 1 2 [/SUP], Bryan Faust[SUP] #[/SUP][SUP] 3 2 4 5 [/SUP], Reuben A Saunders[SUP] #[/SUP][SUP] 3 6 [/SUP], Smriti Sangwan[SUP] #[/SUP][SUP] 3 2 [/SUP], Veronica Rezelj[SUP] #[/SUP][SUP] 7 [/SUP], Nick Hoppe[SUP] 4 5 [/SUP], Morgane Boone[SUP] 3 2 [/SUP], Christian B Billesb?lle[SUP] 4 5 [/SUP], Cristina Puchades[SUP] 5 [/SUP], Caleigh M Azumaya[SUP] 5 [/SUP], Huong T Kratochvil[SUP] 5 [/SUP], Marcell Zimanyi[SUP] 3 2 [/SUP], Ishan Deshpande[SUP] 4 5 [/SUP], Jiahao Liang[SUP] 4 [/SUP], Sasha Dickinson[SUP] 5 [/SUP], Henry C Nguyen[SUP] 5 [/SUP], Cynthia M Chio[SUP] 5 [/SUP], Gregory E Merz[SUP] 5 [/SUP], Michael C Thompson[SUP] 5 [/SUP], Devan Diwanji[SUP] 5 [/SUP], Kaitlin Schaefer[SUP] 5 [/SUP], Aditya A Anand[SUP] 3 2 [/SUP], Niv Dobzinski[SUP] 3 2 [/SUP], Beth Shoshana Zha[SUP] 8 [/SUP], Camille R Simoneau[SUP] 9 10 11 [/SUP], Kristoffer Leon[SUP] 9 10 11 [/SUP], Kris M White[SUP] 12 13 [/SUP], Un Seng Chio[SUP] 5 [/SUP], Meghna Gupta[SUP] 5 [/SUP], Mingliang Jin[SUP] 5 [/SUP], Fei Li[SUP] 5 [/SUP], Yanxin Liu[SUP] 5 [/SUP], Kaihua Zhang[SUP] 5 [/SUP], David Bulkley[SUP] 5 [/SUP], Ming Sun[SUP] 5 [/SUP], Amber M Smith[SUP] 5 [/SUP], Alexandrea N Rizo[SUP] 5 [/SUP], Frank Moss[SUP] 5 [/SUP], Axel F Brilot[SUP] 5 [/SUP], Sergei Pourmal[SUP] 5 [/SUP], Raphael Trenker[SUP] 5 [/SUP], Thomas Pospiech[SUP] 5 [/SUP], Sayan Gupta[SUP] 14 [/SUP], Benjamin Barsi-Rhyne[SUP] 4 [/SUP], Vladislav Belyy[SUP] 3 2 [/SUP], Andrew W Barile-Hill[SUP] 15 [/SUP], Silke Nock[SUP] 3 2 [/SUP], Yuwei Liu[SUP] 3 2 [/SUP], Nevan J Krogan[SUP] 5 6 9 10 [/SUP], Corie Y Ralston[SUP] 14 [/SUP], Danielle L Swaney[SUP] 5 6 9 10 [/SUP], Adolfo Garc?a-Sastre[SUP] 12 13 16 17 [/SUP], Melanie Ott[SUP] 9 10 11 [/SUP], Marco Vignuzzi[SUP] 7 [/SUP], QCRG Structural Biology Consortium; Peter Walter[SUP] 1 2 [/SUP], Aashish Manglik[SUP] 18 5 9 19 [/SUP]
Collaborators, Affiliations
- PMID: 33154106
- DOI: 10.1126/science.abe3255
Abstract
The SARS-CoV-2 virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.