National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
P01-AI13893
United States
Citation
Journal: Science / Year: 2020 Title: De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2. Authors: Thomas W Linsky / Renan Vergara / Nuria Codina / Jorgen W Nelson / Matthew J Walker / Wen Su / Christopher O Barnes / Tien-Ying Hsiang / Katharina Esser-Nobis / Kevin Yu / Z Beau Reneer / ...Authors: Thomas W Linsky / Renan Vergara / Nuria Codina / Jorgen W Nelson / Matthew J Walker / Wen Su / Christopher O Barnes / Tien-Ying Hsiang / Katharina Esser-Nobis / Kevin Yu / Z Beau Reneer / Yixuan J Hou / Tanu Priya / Masaya Mitsumoto / Avery Pong / Uland Y Lau / Marsha L Mason / Jerry Chen / Alex Chen / Tania Berrocal / Hong Peng / Nicole S Clairmont / Javier Castellanos / Yu-Ru Lin / Anna Josephson-Day / Ralph S Baric / Deborah H Fuller / Carl D Walkey / Ted M Ross / Ryan Swanson / Pamela J Bjorkman / Michael Gale / Luis M Blancas-Mejia / Hui-Ling Yen / Daniel-Adriano Silva / 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, ...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 human angiotensin-converting enzyme 2 (hACE2) decoys to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The best monovalent decoy, CTC-445.2, bound with low nanomolar affinity and high specificity to the receptor-binding domain (RBD) of the spike protein. Cryo-electron microscopy (cryo-EM) showed 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, showed ~10-fold improvement in binding. CTC-445.2d potently neutralized 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.
History
Deposition
Oct 29, 2020
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Header (metadata) release
Nov 11, 2020
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Map release
Nov 11, 2020
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Update
Dec 16, 2020
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Current status
Dec 16, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Details: 0.2 mA
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV / Details: 3s blot, 0 blot force.
Details
Monodisperse sample
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Electron microscopy
Microscope
FEI TALOS ARCTICA
Details
3x3 beam tilt collection
Image recording
Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 2250 / Average exposure time: 3.6 sec. / Average electron dose: 60.0 e/Å2
Electron beam
Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
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