|Title||De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.|
|Journal, issue, pages||Science, Vol. 370, Issue 6521, Page 1208-1214, Year 2020|
|Publish date||Dec 4, 2020|
|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 /|
|PubMed 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.|
|External links||Science / PubMed:33154107 / PubMed Central|
|Methods||EM (single particle)|
|Resolution||3.9 - 4.2 Å|
|Keywords||Angiotensin-Converting Enzyme 2 / Animals / Antiviral Agents / COVID-19 / Cricetinae / Cryoelectron Microscopy / Directed Molecular Evolution / Protein Binding / Protein Domains / Protein Engineering / Receptors, Virus / Recombinant Proteins / SARS-CoV-2 / Spike Glycoprotein, Coronavirus / spike protein, SARS-CoV-2 / ANTIVIRAL PROTEIN / ACE2 decoy / mini-protein / inhibitor|
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