De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

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  • Linsky, Thomas W.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Vergara, Renan
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Codina, Nuria
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Nelson, Jorgen W.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Walker, Matthew J.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Su, Wen
    • Other Affiliation: University of Hong Kong
  • Barnes, Christopher O.
    • Other Affiliation: California Institute of Technology
  • Hsiang, Tien-Ying
    • Other Affiliation: University of Washington
  • Esser-Nobis, Katharina
    • Other Affiliation: University of Washington
  • Yu, Kevin
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Reneer, Z. Beau
    • Other Affiliation: University of Georgia
  • Hou, Yixuan J.
    • Other Affiliation: University of Washington
  • Priya, Tanu
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Mitsumoto, Masaya
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Pong, Avery
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Lau, Uland Y.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Mason, Marsha L.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Chen, Jerry
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Chen, Alex
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Berrocal, Tania
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Peng, Hong
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Clairmont, Nicole S.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Castellanos, Javier
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Lin, Yu-Ru
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Josephson-Day, Anna
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Fuller, Deborah H.
    • Other Affiliation: University of Washington
  • Walkey, Carl D.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Ross, Ted M.
    • Other Affiliation: University of Georgia
  • Swanson, Ryan
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Bjorkman, Pamela J.
    • Other Affiliation: California Institute of Technology
  • Gale, Michael
    • Other Affiliation: University of Washington
  • Blancas-Mejia, Luis M.
    • Other Affiliation: Neoleukin Therapeutics Inc.
  • Yen, Hui-Ling
    • Other Affiliation: University of Hong Kong
  • Silva, Daniel-Adriano
    • Other Affiliation: Neoleukin Therapeutics Inc.
Abstract
  • We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.
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  • Article
Rights statement
  • In Copyright
License
  • Attribution 3.0 United States
Journal title
  • Science
Language
  • English
ISSN
  • 0036-8075, 1095-9203

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