@article{2ad70752d5054cacb9274f4c3c64a29a,
title = "Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease",
abstract = "Despite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to have a global impact. Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 spike receptor-binding domain. Here, we investigated the capacity of modified versions of one lead miniprotein, LCB1, to protect against SARS-CoV-2-mediated lung disease in mice. Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung when given as many as 5 days before or 2 days after virus inoculation. Importantly, LCB1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support development of LCB1v1.3 for prevention or treatment of SARS-CoV-2 infection.",
keywords = "COVID-19, SARS-CoV-2, intranasal, mice, miniprotein, pathogenesis, prophylaxis, receptor-binding domain, therapy, variants",
author = "Case, {James Brett} and Chen, {Rita E.} and Longxing Cao and Baoling Ying and Winkler, {Emma S.} and Max Johnson and Inna Goreshnik and Pham, {Minh N.} and Swathi Shrihari and Kafai, {Natasha M.} and Bailey, {Adam L.} and Xuping Xie and Shi, {Pei Yong} and Rashmi Ravichandran and Lauren Carter and Lance Stewart and David Baker and Diamond, {Michael S.}",
note = "Funding Information: This study was supported by NIH grants ( R01 AI157155 , Al134907 , and UL1TR001439 ), the Defense Advanced Research Project Agency ( HR001117S0019 and HR0011835403 contract FA8750-17-C-0219 ), the Audacious Project at the Institute for Protein Design (L. Carter and D.B.), funding from E. and W. Schmidt by recommendation of the Schmidt Futures program (L. Carter, R.R., I.G., and D.B.), the Open Philanthropy Project Improving Protein Design Fund (D.B.), Bill and Melinda Gates Foundation # OPP1156262 (L.S., L. Carter, M.N.P., R.R., and D.B.), and a gift from the Granieri family (M.J.). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship, E.S.W. is supported by F30 AI152327 , N.M.K. is supported by T32 AI007172 , and P.-Y.S. is supported by awards from the Sealy and Smith Foundation , the Kleberg Foundation , the John S. Dunn Foundation , the Amon G. Carter Foundation , the Gilson Longenbaugh Foundation , and the Summerfield Robert Foundation . We thank Lisa Kozodoy and Lexi Walls for support in development of ELISA assays; Cassie Ogohara and Michael Murphy for support in protein production and purification; the Pulmonary Morphology Core at Washington University School of Medicine for tissue sectioning and slide preparation; and SCIREQ Inc. for providing the flexiVent pulmonary mechanics research platform and analysis software. Funding Information: This study was supported by NIH grants (R01 AI157155, Al134907, and UL1TR001439), the Defense Advanced Research Project Agency (HR001117S0019 and HR0011835403 contract FA8750-17-C-0219), the Audacious Project at the Institute for Protein Design (L. Carter and D.B.), funding from E. and W. Schmidt by recommendation of the Schmidt Futures program (L. Carter, R.R. I.G. and D.B.), the Open Philanthropy Project Improving Protein Design Fund (D.B.), Bill and Melinda Gates Foundation #OPP1156262 (L.S. L. Carter, M.N.P. R.R. and D.B.), and a gift from the Granieri family (M.J.). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship, E.S.W. is supported by F30 AI152327, N.M.K. is supported by T32 AI007172, and P.-Y.S. is supported by awards from the Sealy and Smith Foundation, the Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Gilson Longenbaugh Foundation, and the Summerfield Robert Foundation. We thank Lisa Kozodoy and Lexi Walls for support in development of ELISA assays; Cassie Ogohara and Michael Murphy for support in protein production and purification; the Pulmonary Morphology Core at Washington University School of Medicine for tissue sectioning and slide preparation; and SCIREQ Inc. for providing the flexiVent pulmonary mechanics research platform and analysis software. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material. Some figure components were created using software from Biorender.com. J.B.C. L.S. D.B. and M.S.D. designed the research. J.B.C. R.E.C. E.S.W. S.S. and N.M.K. performed mouse experiments and clinical analyses. J.B.C. and B.Y. performed viral burden analysis. J.B.C. and E.S.W. performed pulmonary mechanics analysis. A.L.B. analyzed the tissue sections for histopathology. J.B.C. and R.E.C. performed neutralization analysis. L. Cao optimized protein designs, generated computational models, and performed BLI analysis. L. Carter and R.R. purified and prepared the miniproteins. M.J. M.N.P. I.G. and L.S. developed and performed ELISA analysis. X.X. and P.-Y.S. provided the recombinant virus strains. J.B.C. and M.S.D. wrote the initial draft, with other authors providing editorial comments and helpful discussions about the research. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation, and is on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. L. Cao, I.G. L.S. J.B.C. M.S.D. and D.B. are coinventors on a provisional patent application that incorporates discoveries described in this manuscript. D.B. is a cofounder of Neoleukin Therapeutics. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
day = "14",
doi = "10.1016/j.chom.2021.06.008",
language = "English (US)",
volume = "29",
pages = "1151--1161.e5",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "7",
}