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

TL;DR

Researchers designed new agonists that fine-tune G-CSFR signaling to control stem cell differentiation and proliferation more effectively than natural cytokines.

Contribution

The study introduces de novo-designed agonists that selectively modulate G-CSFR signaling with enhanced stability and specificity.

Findings

Design agonists outcompete native G-CSF and bias cells toward granulopoietic differentiation.

The agonists modulate signal transduction kinetics and gene expression with minimal immunomodulatory effects.

Designed agonists show hyper-thermostability and selective activation of hematopoietic gene sets.

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.

Skokowa, ElGamacy, and colleagues report the design and characterization of protein agonists that fine-tune granulocyte-colony-stimulating factor receptor activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. The agonists differentially modulate the kinetics and amplitudes of signal transduction pathways and effects on cell proliferation and differentiation.

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