De novo design of picomolar SARS-CoV-2 miniprotein inhibitors.
De novo design of picomolar SARS-CoV-2 miniprotein inhibitors.
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皮摩尔SARS-COV-2小蛋白抑制剂的从头设计。
DOI：
10.1126/science.abd9909
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发表时间：
2020-10-23
期刊：
影响因子：
--
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Cao L;Goreshnik I;Coventry B;Case JB;Miller L;Kozodoy L;Chen RE;Carter L;Walls AC;Park YJ;Strauch EM;Stewart L;Diamond MS;Veesler D;Baker D
严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）被刺突修饰，当这些刺突与宿主血管紧张素转换酶2（ACE 2）受体结合时，病毒进入细胞就开始了。许多单克隆抗体疗法的发展目标的刺突蛋白。Cao等人设计了小的、稳定的蛋白质，它们紧密地结合到刺突上，并阻止它与ACE 2结合。最佳设计以非常高的亲和力结合并防止SARS-CoV-2感染哺乳动物Vero E6细胞。冷冻电子显微镜显示，两种最有效的抑制剂的结构与计算模型几乎相同。与抗体不同，微蛋白不需要在哺乳动物细胞中表达，并且它们的小尺寸和高稳定性可以允许制剂直接递送至鼻或呼吸系统。科学，本期第426页设计的小蛋白与SARS-CoV-2刺突蛋白紧密结合，并阻止与宿主细胞受体结合。针对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）刺突蛋白与人血管紧张素转换酶2（ACE 2）受体之间的相互作用是一种有前途的治疗策略。我们使用两种从头设计方法设计抑制剂。计算机生成的支架要么围绕与刺突受体结合域（RBD）相互作用的ACE 2螺旋构建，要么对接RBD以识别新的结合模式，并且其氨基酸序列的设计旨在优化靶点结合、折叠和稳定性。10种设计结合RBD，亲和力范围从100皮摩尔到10纳摩尔，并阻断SARS-CoV-2感染Vero E6细胞，半数抑制浓度（IC 50）值在24皮摩尔和35纳摩尔之间。最有效的，具有新的结合模式，是56和64个残基的蛋白质（IC 50 ~ 0.16纳克/毫升）。与SARS-CoV-2刺突胞外域三聚体复合的这些微结合物的冷冻电子显微镜结构与所有三个RBD结合几乎与计算模型相同。这些超稳定的minibinders为SARS-CoV-2治疗提供了起点。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the host angiotensin-converting enzyme 2 (ACE2) receptor. Many monoclonal antibody therapies in development target the spike proteins. Cao et al. designed small, stable proteins that bind tightly to the spike and block it from binding to ACE2. The best designs bind with very high affinity and prevent SARS-CoV-2 infection of mammalian Vero E6 cells. Cryo–electron microscopy shows that the structures of the two most potent inhibitors are nearly identical to the computational models. Unlike antibodies, the miniproteins do not require expression in mammalian cells, and their small size and high stability may allow formulation for direct delivery to the nasal or respiratory system. Science, this issue p. 426 Designed miniproteins bind tightly to the SARS-CoV-2 spike protein and prevent binding to the host cell receptor. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with the spike receptor binding domain (RBD) or docked against the RBD to identify new binding modes, and their amino acid sequences were designed to optimize target binding, folding, and stability. Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells with median inhibitory concentration (IC50) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC50 ~ 0.16 nanograms per milliliter). Cryo–electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
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：
56.9
作者：
Yan, Renhong;Zhang, Yuanyuan;Zhou, Qiang
通讯作者：
Zhou, Qiang
影响因子：
64.8
作者：
Dou J;Vorobieva AA;Sheffler W;Doyle LA;Park H;Bick MJ;Mao B;Foight GW;Lee MY;Gagnon LA;Carter L;Sankaran B;Ovchinnikov S;Marcos E;Huang PS;Vaughan JC;Stoddard BL;Baker D
通讯作者：
Baker D