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

doi:10.1126/science.abe0075

GSTDTAP > 气候变化

DOI	10.1126/science.abe0075
	De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2
	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
	2020-12-04
发表期刊	Science
出版年	2020
英文摘要	Many efforts to develop therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are focused on the interaction between the spike protein, which decorates the surface of the virus, and its host receptor, human angiotensin-converting enzyme 2 (hACE2). Linsky et al. describe a de novo design strategy that allowed them to engineer decoy proteins that bind to the spike protein by replicating the hACE2 interface. The best decoy, CTC-445, bound with low nanomolar affinity, and selection of viral mutants that decrease binding is unlikely because this would also affect binding to hACE2. A bivalent version of CTC-445 bound even more tightly, neutralized SARS-CoV-2 infection of cells, and protected hamsters from a SARS-CoV-2 challenge. The stable decoy has the potential for respiratory therapeutic delivery. Science , this issue p. [1208][1] 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. [1]: /lookup/doi/10.1126/science.abe0075
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/305838
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Thomas W. Linsky,Renan Vergara,Nuria Codina,et al. De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2[J]. Science,2020.
APA	Thomas W. Linsky.,Renan Vergara.,Nuria Codina.,Jorgen W. Nelson.,Matthew J. Walker.,...&Daniel-Adriano Silva.(2020).De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.Science.
MLA	Thomas W. Linsky,et al."De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2".Science (2020).