10.17615/2F24-RY10
Clairmont, Nicole S.
Lau, Uland Y.
Peng, Hong
Chen, Alex
Barnes, Christopher O.
Fuller, Deborah H.
Yen, Hui-Ling
Lin, Yu-Ru
Bjorkman, Pamela J.
Castellanos, Javier
Yu, Kevin
Chen, Jerry
Mason, Marsha L.
Swanson, Ryan
Reneer, Z. Beau
Baric, Ralph S.
Blancas-Mejia, Luis M.
Silva, Daniel-Adriano
Linsky, Thomas W.
Walkey, Carl D.
Josephson-Day, Anna
Priya, Tanu
Vergara, Renan
Nelson, Jorgen W.
Hou, Yixuan J.
Pong, Avery
Berrocal, Tania
Esser-Nobis, Katharina
Hsiang, Tien-Ying
Ross, Ted M.
Su, Wen
Mitsumoto, Masaya
Walker, Matthew J.
Gale, Michael
Codina, Nuria
De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2
The University of North Carolina at Chapel Hill University Libraries
2020
Article
English
In Copyright
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.