Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2.
Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2.
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DOI：
10.1126/science.abc0870
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发表时间：
2020-09-04
期刊：
影响因子：
--
通讯作者：
Procko E
中科院分区：
文献类型：
--
作者：
Chan KK;Dorosky D;Sharma P;Abbasi SA;Dye JM;Kranz DM;Herbert AS;Procko E
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）要进入人体细胞，病毒表面的刺突蛋白必须与宿主受体蛋白血管紧张素转换酶2 （ACE2）结合。这种受体的可溶性版本正在被研究用于治疗。Chan等人利用深度诱变技术鉴定了与刺突蛋白结合更紧密的ACE2突变体，并结合突变进一步提高了结合亲和力（见DeKosky的观点）。一种有希望的变体被设计成一种稳定的二聚体，对刺突蛋白具有结合亲和力；它与中和抗体相当，并在基于细胞的测定中中和了SARS-CoV-2和SARS-CoV-1。此外，与天然受体的相似性可能会限制病毒逃逸的可能性。《科学》，本期第1261页；另见p.基于深度诱变的ACE2变体在结合SARS-CoV-2刺突蛋白方面远远优于天然受体。严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的刺突(S)蛋白与宿主细胞上的血管紧张素转换酶2 （ACE2）结合，启动进入，可溶性ACE2是一种治疗候选者，通过充当诱饵来中和感染。通过深度诱变，ACE2中增加S结合的突变在相互作用表面、天冬酰胺90糖基化基序和埋藏位点被发现。突变景观为理解ACE2和S之间相互作用的特异性以及设计高亲和力诱饵受体提供了蓝图。结合突变使ACE2变体具有与单克隆抗体相媲美的亲和力。稳定的二聚体变体在体外表现出有效的SARS-CoV-2和-1中和。工程受体具有催化活性，其与天然受体的密切相似性可能限制病毒逃逸的可能性。
For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter human cells, the spike protein on the surface of the virus must bind to the host receptor protein, angiotensin-converting enzyme 2 (ACE2). A soluble version of the receptor is being explored as a therapeutic. Chan et al. used deep mutagenesis to identify ACE2 mutants that bind more tightly to the spike protein and combined mutations to further increase binding affinity (see the Perspective by DeKosky). A promising variant was engineered to be a stable dimer that has a binding affinity for the spike protein; it is comparable with neutralizing antibodies and neutralized both SARS-CoV-2 and SARS-CoV-1 in a cell-based assay. In addition, the similarity to the natural receptor may limit the possibility for viral escape. Science, this issue p. 1261; see also p. A variant of ACE2 based on deep mutagenesis far outcompetes the natural receptor in binding the SARS-CoV-2 spike protein. The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. By using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the asparagine 90–glycosylation motif and at buried sites. The mutational landscape provides a blueprint for understanding the specificity of the interaction between ACE2 and S and for engineering high-affinity decoy receptors. Combining mutations gives ACE2 variants with affinities that rival those of monoclonal antibodies. A stable dimeric variant shows potent SARS-CoV-2 and -1 neutralization in vitro. The engineered receptor is catalytically active, and its close similarity with the native receptor may limit the potential for viral escape.
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影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
影响因子：
48
作者：
Fowler, Douglas M.;Fields, Stanley
通讯作者：
Fields, Stanley
DOI：
10.1016/s0140-6736(03)13077-2
发表时间：
2003-04-19
期刊：
Lancet (London, England)
影响因子：
--
作者：
Peiris JS;Lai ST;Poon LL;Guan Y;Yam LY;Lim W;Nicholls J;Yee WK;Yan WW;Cheung MT;Cheng VC;Chan KH;Tsang DN;Yung RW;Ng TK;Yuen KY;SARS study group
通讯作者：
SARS study group
DOI：
10.4049/jimmunol.1800343
发表时间：
2018-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Heredia JD;Park J;Brubaker RJ;Szymanski SK;Gill KS;Procko E
通讯作者：
Procko E
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin