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Cryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an anti-SARS-CoV-2 DARPin (Local refinement of FSR22 and RBD)Cryo-EM structure of SARS-CoV-2 spike in complex with FSR22, an anti-SARS-CoV-2 DARPin (Local refinement of FSR22 and RBD)
Structural highlights
Publication Abstract from PubMedWe 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. A potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins.,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 Nat Chem Biol. 2023 Mar;19(3):284-291. doi: 10.1038/s41589-022-01193-2. Epub 2022 , Nov 21. PMID:36411391[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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