Tuning of G-CSFR signaling by de novo-designed agonists.

ABSTRACT: Enhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune granulocyte-colony-stimulating factor receptor (G-CSFR) activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. Using design agonists, we study the impact of varying the receptor-binding affinity and dimerization geometry on receptor association, downstream signaling, and cellular response. Hence, we achieved agonists with altered signaling specificities that are hyper-thermostable, can outcompete the native ligand (G-CSF), and bias cells toward granulopoietic differentiation over triggering proliferation. Further

SUBMITTER: Ullrich T 

PROVIDER: S-EPMC12628175 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature