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A potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins.
Chonira, Vikas; Kwon, Young D; Gorman, Jason; Case, James Brett; Ku, Zhiqiang; Simeon, Rudo; Casner, Ryan G; Harris, Darcy R; Olia, Adam S; Stephens, Tyler; Shapiro, Lawrence; Bender, Michael F; Boyd, Hannah; Teng, I-Ting; Tsybovsky, Yaroslav; Krammer, Florian; Zhang, Ningyan; Diamond, Michael S; Kwong, Peter D; An, Zhiqiang; Chen, Zhilei.
Afiliação
  • Chonira V; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX, USA.
  • Kwon YD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Gorman J; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Case JB; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
  • Ku Z; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • Simeon R; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX, USA.
  • Casner RG; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
  • Harris DR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Olia AS; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Stephens T; Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Shapiro L; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
  • Bender MF; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Boyd H; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • Teng IT; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Tsybovsky Y; Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Krammer F; Department of Microbiology, Icahn School of Medicine at Mount Sinai (ISMMS), New York City, NY, USA.
  • Zhang N; Department of Pathology, Molecular and Cell based Medicine, ISMMS, New York City, NY, USA.
  • Diamond MS; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • Kwong PD; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. mdiamond@wustl.edu.
  • An Z; Department of Pathology and Immunology, Department of Molecular Microbiology, and The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA. mdiamond@wustl.edu.
  • Chen Z; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. pkwong@mail.nih.gov.
Nat Chem Biol ; 19(3): 284-291, 2023 03.
Article em En | MEDLINE | ID: mdl-36411391
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 IC50 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: SARS-CoV-2 / COVID-19 Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: SARS-CoV-2 / COVID-19 Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article