Journal
CELL
Volume 185, Issue 8, Pages 1414-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2022.02.025
Keywords
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Categories
Funding
- National Institute of Allergy and Infectious Diseases (NIAID) [R37-AI051321]
- Mathers Charitable Foundation
- NIAID [R01 AI132178, R01 AI132178-04S1]
- Bill & Melinda Gates Foundation [OPP1113682]
- North Carolina Policy Collaboratory at University of North Carolina at Chapel Hill
- North Carolina Coronavirus Relief Fund by the North Carolina General Assembly
- Stanford Immunology Program Training Grant [5T32AI07290-33]
- Stanford Immunology and Rheumatology Training Grant [5T32AR050942-15]
- NIH grant [T32 AI007502-23]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P30GM133894]
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This study presents a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics. The researchers generated combinatorial matrices of single-chain bispecific ligands and discovered that this approach can lead to the engineering of surrogate ligands that compel assembly of non-natural receptor heterodimers. The findings demonstrate the generalizability of this approach for the discovery of diversified agonists for various ligand-receptor systems.
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-2R:VHH 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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