tetano
Editor, Senior Moderator
Sci Transl Med
. 2022 Apr 12;eabn1252.
doi: 10.1126/scitranslmed.abn1252. Online ahead of print.
Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice
Andrew C Hunt[SUP] #[/SUP][SUP] 1 [/SUP], James Brett Case[SUP] #[/SUP], Young-Jun Park[SUP] #[/SUP][SUP] 2 [/SUP], Longxing Cao[SUP] #[/SUP][SUP] 2 3 [/SUP], Kejia Wu[SUP] #[/SUP][SUP] 2 3 [/SUP], Alexandra C Walls[SUP] #[/SUP][SUP] 2 4 [/SUP], Zhuoming Liu[SUP] 5 [/SUP], John E Bowen[SUP] 2 [/SUP], Hsien-Wei Yeh[SUP] 2 3 [/SUP], Shally Saini[SUP] 2 6 [/SUP], Louisa Helms[SUP] 6 7 8 9 [/SUP], Yan Ting Zhao[SUP] 2 6 10 [/SUP], Tien-Ying Hsiang[SUP] 11 [/SUP], Tyler N Starr[SUP] 12 [/SUP], Inna Goreshnik[SUP] 2 3 [/SUP], Lisa Kozodoy[SUP] 2 3 [/SUP], Lauren Carter[SUP] 2 3 [/SUP], Rashmi Ravichandran[SUP] 2 3 [/SUP], Lydia B Green[SUP] 13 [/SUP], Wadim L Matochko[SUP] 13 [/SUP], Christy A Thomson[SUP] 13 [/SUP], Bastian Vögeli[SUP] 1 14 [/SUP], Antje Krüger[SUP] 1 [/SUP], Laura A VanBlargan, Rita E Chen[SUP] 15 [/SUP], Baoling Ying, Adam L Bailey[SUP] 15 16 [/SUP], Natasha M Kafai[SUP] 15 [/SUP], Scott E Boyken[SUP] 2 3 [/SUP], Ajasja Ljubetič[SUP] 2 3 17 [/SUP], Natasha Edman[SUP] 2 3 18 19 [/SUP], George Ueda[SUP] 2 3 [/SUP], Cameron M Chow[SUP] 2 3 20 [/SUP], Max Johnson[SUP] 2 3 [/SUP], Amin Addetia[SUP] 2 21 [/SUP], Mary Jane Navarro[SUP] 2 [/SUP], Nuttada Panpradist[SUP] 22 [/SUP], Michael Gale Jr[SUP] 11 [/SUP], Benjamin S Freedman[SUP] 6 7 8 22 9 [/SUP], Jesse D Bloom[SUP] 4 12 23 [/SUP], Hannele Ruohola-Baker[SUP] 2 6 10 22 [/SUP], Sean P J Whelan[SUP] 5 [/SUP], Lance Stewart[SUP] 2 3 [/SUP], Michael S Diamond[SUP] 5 15 24 [/SUP], David Veesler[SUP] 2 4 [/SUP], Michael C Jewett[SUP] 1 25 26 [/SUP], David Baker[SUP] 2 3 4 [/SUP]
Affiliations
Abstract
New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy with a homo-trimeric version of the 75-residue angiotensin converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. In the cryo-electron microscopy structure, TRI2 formed a tripod on top of the spike protein which engaged all three receptor binding domains (RBDs) simultaneously as in the design model. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than that of monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies and native receptor traps. By comparison, the designed proteins have resistance to viral escape and antigenic drift by construction, precisely tuned avidity, and greatly reduced chance of autoimmune responses.
. 2022 Apr 12;eabn1252.
doi: 10.1126/scitranslmed.abn1252. Online ahead of print.
Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice
Andrew C Hunt[SUP] #[/SUP][SUP] 1 [/SUP], James Brett Case[SUP] #[/SUP], Young-Jun Park[SUP] #[/SUP][SUP] 2 [/SUP], Longxing Cao[SUP] #[/SUP][SUP] 2 3 [/SUP], Kejia Wu[SUP] #[/SUP][SUP] 2 3 [/SUP], Alexandra C Walls[SUP] #[/SUP][SUP] 2 4 [/SUP], Zhuoming Liu[SUP] 5 [/SUP], John E Bowen[SUP] 2 [/SUP], Hsien-Wei Yeh[SUP] 2 3 [/SUP], Shally Saini[SUP] 2 6 [/SUP], Louisa Helms[SUP] 6 7 8 9 [/SUP], Yan Ting Zhao[SUP] 2 6 10 [/SUP], Tien-Ying Hsiang[SUP] 11 [/SUP], Tyler N Starr[SUP] 12 [/SUP], Inna Goreshnik[SUP] 2 3 [/SUP], Lisa Kozodoy[SUP] 2 3 [/SUP], Lauren Carter[SUP] 2 3 [/SUP], Rashmi Ravichandran[SUP] 2 3 [/SUP], Lydia B Green[SUP] 13 [/SUP], Wadim L Matochko[SUP] 13 [/SUP], Christy A Thomson[SUP] 13 [/SUP], Bastian Vögeli[SUP] 1 14 [/SUP], Antje Krüger[SUP] 1 [/SUP], Laura A VanBlargan, Rita E Chen[SUP] 15 [/SUP], Baoling Ying, Adam L Bailey[SUP] 15 16 [/SUP], Natasha M Kafai[SUP] 15 [/SUP], Scott E Boyken[SUP] 2 3 [/SUP], Ajasja Ljubetič[SUP] 2 3 17 [/SUP], Natasha Edman[SUP] 2 3 18 19 [/SUP], George Ueda[SUP] 2 3 [/SUP], Cameron M Chow[SUP] 2 3 20 [/SUP], Max Johnson[SUP] 2 3 [/SUP], Amin Addetia[SUP] 2 21 [/SUP], Mary Jane Navarro[SUP] 2 [/SUP], Nuttada Panpradist[SUP] 22 [/SUP], Michael Gale Jr[SUP] 11 [/SUP], Benjamin S Freedman[SUP] 6 7 8 22 9 [/SUP], Jesse D Bloom[SUP] 4 12 23 [/SUP], Hannele Ruohola-Baker[SUP] 2 6 10 22 [/SUP], Sean P J Whelan[SUP] 5 [/SUP], Lance Stewart[SUP] 2 3 [/SUP], Michael S Diamond[SUP] 5 15 24 [/SUP], David Veesler[SUP] 2 4 [/SUP], Michael C Jewett[SUP] 1 25 26 [/SUP], David Baker[SUP] 2 3 4 [/SUP]
Affiliations
- PMID: 35412328
- DOI: 10.1126/scitranslmed.abn1252
Abstract
New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy with a homo-trimeric version of the 75-residue angiotensin converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. In the cryo-electron microscopy structure, TRI2 formed a tripod on top of the spike protein which engaged all three receptor binding domains (RBDs) simultaneously as in the design model. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than that of monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies and native receptor traps. By comparison, the designed proteins have resistance to viral escape and antigenic drift by construction, precisely tuned avidity, and greatly reduced chance of autoimmune responses.