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Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Science 2020 ; 370 (6521): 1208-1214 Nephropedia Template TP
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De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2 #MMPMID33154107
Linsky TW; Vergara R; Codina N; Nelson JW; Walker MJ; Su W; Barnes CO; Hsiang TY; Esser-Nobis K; Yu K; Reneer ZB; Hou YJ; Priya T; Mitsumoto M; Pong A; Lau UY; Mason ML; Chen J; Chen A; Berrocal T; Peng H; Clairmont NS; Castellanos J; Lin YR; Josephson-Day A; Baric RS; Fuller DH; Walkey CD; Ross TM; Swanson R; Bjorkman PJ; Gale M Jr; Blancas-Mejia LM; Yen HL; Silva DA
Science 2020[Dec]; 370 (6521): 1208-1214 PMID33154107show ga
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.