A potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins

被引：11

作者：

Chonira, Vikas ^{[1
]}

Kwon, Young D. ^{[2
]}

Gorman, Jason ^{[2
]}

Case, James Brett ^{[3
]}

Ke, Zhiqiang ^{[4
]}

Simeon, Rudo ^{[1
]}

Cosner, Ryan G. ^{[5
]}

Harris, Darcy R. ^{[2
]}

Olia, Adam S. ^{[2
]}

Stephens, Tyler ^{[6
]}

Shapiro, Lawrence ^{[5
]}

Bender, Michael F. ^{[2
]}

Boyd, Hannah ^{[4
]}

Teng, I-Ting ^{[2
]}

Tsybovsky, Yaroslav ^{[6
]}

Krammer, Florian ^{[7
,8
]}

Zhang, Ningyan ^{[4
]}

Diamond, Michael S. ^{[3
,9
,10
]}

Kwong, Peter D. ^{[2
]}

An, Zhiqiang ^{[4
]}

Chen, Zhilei ^{[1
]}

机构：

[1] Texas A&M Univ, Dept Microbial Pathogenesis & Immunol, Hlth Sci Ctr, Bryan, TX 77807 USA

[2] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[3] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[4] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Texas Therapeut Inst, Houston, TX 77030 USA

[5] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA

[6] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Vaccine Res Ctr, Electron Microscopy Unit,Canc Res Technol Program, Frederick, MD USA

[7] Icahn Sch Med Mt Sinai ISMMS, Dept Microbiol, New York, NY USA

[8] ISMMS, Dept Pathol Mol & Cell Based Med, New York, NY USA

[9] Washington Univ, Sch Med, Dept Pathol & Immunol, Dept Mol Microbiol, St Louis, MO 63110 USA

[10] Washington Univ, Sch Med, Andrew M & Jane M Bursky Ctr Human Immunol & Immu, St Louis, MO 63110 USA

来源：

NATURE CHEMICAL BIOLOGY | 2023年 / 19卷 / 03期

基金：

美国国家卫生研究院;

关键词：

DOMAIN; MODEL; ACE2;

D O I：

10.1038/s41589-022-01193-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC(50 )values of 3.4, 2.2 and 7.4 ng ml(-1) for FSR16m. Cryo-EM structures revealed that these DARPins recognize a region of the receptor-binding domain (residues 456, 475, 486, 487 and 489) overlapping a critical portion of the angiotensin-converting enzyme 2 (ACE2)-binding surface. K18-hACE2 transgenic mice inoculated with B.1.617.2 and receiving intranasally administered FSR16m showed less weight loss and 10-100-fold lower viral burden in upper and lower respiratory tracts. The strong and broad neutralization potency makes FSR16m and FSR22 promising candidates for the prevention and treatment of infection by SARS-CoV-2.

引用

页码：284 / +

页数：15

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