1. A strategy to design protein-based antagonists against type I cytokine receptors.
- Author
-
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, and ElGamacy, Mohammad
- Subjects
GRANULOCYTE-colony stimulating factor ,ACUTE myeloid leukemia ,HEMATOPOIETIC stem cells ,HUMAN stem cells ,PROTEIN engineering - Abstract
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. Protein-based therapies have been developed to block cytokine signaling in a range of different diseases. These authors use a computational protein design approach to develop novel cytokine receptor antagonists and show that the designed proteins can inhibit G-CSFR activation in a cell model of acute myeloid leukemia. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF