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Facile discovery of surrogate cytokine agonists.
Yen, Michelle; Ren, Junming; Liu, Qingxiang; Glassman, Caleb R; Sheahan, Timothy P; Picton, Lora K; Moreira, Fernando R; Rustagi, Arjun; Jude, Kevin M; Zhao, Xiang; Blish, Catherine A; Baric, Ralph S; Su, Leon L; Garcia, K Christopher.
  • Yen M; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Ren J; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Liu Q; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Glassman CR; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Sheahan TP; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Picton LK; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Moreira FR; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Rustagi A; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Jude KM; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Zhao X; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Blish CA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
  • Baric RS; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Su LL; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Garcia KC; Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
Cell ; 185(8): 1414-1430.e19, 2022 04 14.
Article in English | MEDLINE | ID: covidwho-1757193
ABSTRACT
Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2RVHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cytokines / COVID-19 Limits: Humans Language: English Journal: Cell Year: 2022 Document Type: Article Affiliation country: J.cell.2022.02.025

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cytokines / COVID-19 Limits: Humans Language: English Journal: Cell Year: 2022 Document Type: Article Affiliation country: J.cell.2022.02.025