A strategy to design protein-based antagonists against type I cytokine receptors

Excessive cytokine signaling resulting from dysregulation of a cytokine or its receptor can be a main driver of cancer, autoimmune, or hematopoietic disorders. Here, we leverage protein design to create tailored cytokine receptor blockers with idealized properties. Specifically, we aimed to tackle t...

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Bibliographic Details
Published in:PLoS biology 2024-11, Vol.22 (11), p.e3002883
Main Authors: Ullrich, Timo, Klimenkova, Olga, Pollmann, Christoph, Lasram, Asma, Hatskovska, Valeriia, Maksymenko, Kateryna, Milijaš-Jotić, Matej, Schenk, Lukas, Lengerke, Claudia, Hartmann, Marcus D, Piehler, Jacob, Skokowa, Julia, ElGamacy, Mohammad
Format: Article
Language:English
Subjects:
Antagonists (Biochemistry)
Biology and Life Sciences
Cell receptors
Crystallography, X-Ray - methods
Cytokines
Cytokines - metabolism
Drug Design
Health aspects
HEK293 Cells
Hematopoietic Stem Cells - drug effects
Hematopoietic Stem Cells - metabolism
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - metabolism
Medicine and Health Sciences
Methods
Physical Sciences
Product development
Protein Binding
Protein engineering
Protein Engineering - methods
Proteins
Receptors, Granulocyte Colony-Stimulating Factor - metabolism
Research and Analysis Methods
Signal Transduction - drug effects
Stem cells
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Summary:Excessive cytokine signaling resulting from dysregulation of a cytokine or its receptor can be a main driver of cancer, autoimmune, or hematopoietic disorders. Here, we leverage protein design to create tailored cytokine receptor blockers with idealized properties. Specifically, we aimed to tackle the granulocyte-colony stimulating factor receptor (G-CSFR), a mediator of different types of leukemia and autoinflammatory diseases. By modifying designed G-CSFR binders, we engineered hyper-stable proteins that function as nanomolar signaling antagonists. X-ray crystallography showed atomic-level agreement with the experimental structure of an exemplary design. Furthermore, the most potent design blocks G-CSFR in acute myeloid leukemia cells and primary human hematopoietic stem cells. Thus, the resulting designs can be used for inhibiting or homing to G-CSFR-expressing cells. Our results also demonstrate that similarly designed cytokine mimics can be used to derive antagonists to tackle other type I cytokine receptors.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3002883