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

Authors :: Chonira V
Kwon YD
Gorman J
Case JB
Ku Z
Simeon R
Casner RG
Harris DR
Olia AS
Stephens T
Shapiro L
Bender MF
Boyd H
Teng IT
Tsybovsky Y
Krammer F
Zhang N
Diamond MS
Kwong PD
An Z
Chen Z
Source :: Nature chemical biology [Nat Chem Biol] 2023 Mar; Vol. 19 (3), pp. 284-291. Date of Electronic Publication: 2022 Nov 21.
Publication Year :: 2023
Abstract: 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 <subscript>50</subscript> values of 3.4, 2.2 and 7.4 ng ml <superscript>-1</superscript> 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.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)