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TitleA potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins.
Journal, issue, pagesNat Chem Biol, Vol. 19, Issue 3, Page 284-291, Year 2023
Publish dateNov 21, 2022
AuthorsVikas Chonira / Young D Kwon / Jason Gorman / James Brett Case / Zhiqiang Ku / Rudo Simeon / Ryan G Casner / Darcy R Harris / Adam S Olia / Tyler Stephens / Lawrence Shapiro / Michael F Bender / Hannah Boyd / I-Ting Teng / Yaroslav Tsybovsky / Florian Krammer / Ningyan Zhang / Michael S Diamond / Peter D Kwong / Zhiqiang An / Zhilei Chen /
PubMed AbstractWe 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 ...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 values of 3.4, 2.2 and 7.4 ng ml 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.
External linksNat Chem Biol / PubMed:36411391 / PubMed Central
MethodsEM (single particle)
Resolution3.51 - 4.26 Å
Structure data

26200

7tyz

EMDB-26200, PDB-7tyz:
Cryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an anti-SARS-CoV-2 DARPin
Method: EM (single particle) / Resolution: 3.51 Å

26201

7tz0

EMDB-26201, PDB-7tz0:
Cryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an anti-SARS-CoV-2 DARPin (Local refinement of FSR22 and RBD)
Method: EM (single particle) / Resolution: 4.17 Å

27749

8dw2

EMDB-27749, PDB-8dw2:
Cryo-EM structure of SARS-CoV-2 RBD in complex with anti-SARS-CoV-2 DARPin,SR22, and two antibody Fabs, S309 and CR3022
Method: EM (single particle) / Resolution: 4.11 Å

27750

8dw3

EMDB-27750, PDB-8dw3:
Cryo-EM structure of SARS-CoV-2 RBD in complex with anti-SARS-CoV-2 DARPin,SR16m, and two antibody Fabs, S309 and CR3022
Method: EM (single particle) / Resolution: 4.26 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • escherichia phage ecszw-2escherichia coli (virus)
  • escherichia phage ecszw-2 (virus)
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/ANTIVIRAL PROTEIN / DARPins / Anti-SARS-CoV-2 / therapeutics / COVID-19 / VIRAL PROTEIN-ANTIVIRAL PROTEIN complex / VIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM complex

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