Work

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

Year: 2025

Type: article

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. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways and gene expression patterns. In contrast to G-CSF, they achieve more selective activation of gene sets with hematopoietic functions, with minimal unwanted effects on immunomodulatory signaling. These findings demonstrate the potential of dissecting the complex G-CSFR signaling, and they open up ways for new therapeutic applications for designed cytokines.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2025.08.031