De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.
De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.
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DOI：
10.1126/science.abe0075
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发表时间：
2020-12-04
期刊：
影响因子：
--
通讯作者：
Silva DA
中科院分区：
文献类型：
--
作者：
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
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 Designed de novo protein decoys neutralize SARS-CoV-2 in vitro and in vivo and are resilient to viral mutational escape. 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.
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影响因子：
64.8
作者：
Chevalier A;Silva DA;Rocklin GJ;Hicks DR;Vergara R;Murapa P;Bernard SM;Zhang L;Lam KH;Yao G;Bahl CD;Miyashita SI;Goreshnik I;Fuller JT;Koday MT;Jenkins CM;Colvin T;Carter L;Bohn A;Bryan CM;Fernández-Velasco DA;Stewart L;Dong M;Huang X;Jin R;Wilson IA;Fuller DH;Baker D
通讯作者：
Baker D
DOI：
10.4049/jimmunol.2000583
发表时间：
2020-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Alsoussi WB;Turner JS;Case JB;Zhao H;Schmitz AJ;Zhou JQ;Chen RE;Lei T;Rizk AA;McIntire KM;Winkler ES;Fox JM;Kafai NM;Thackray LB;Hassan AO;Amanat F;Krammer F;Watson CT;Kleinstein SH;Fremont DH;Diamond MS;Ellebedy AH
通讯作者：
Ellebedy AH
影响因子：
20.3
作者：
Gao, GP;Lebherz, C;Wilson, JM
通讯作者：
Wilson, JM
影响因子：
5.4
作者：
Chen, Wen-Hsiang;Strych, Ulrich;Bottazzi, Maria Elena
通讯作者：
Bottazzi, Maria Elena
影响因子：
6.7
作者：
Doud, Michael B.;Hensley, Scott E.;Bloom, Jesse D.
通讯作者：
Bloom, Jesse D.