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

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.

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Publication Details

Journal
Molecular Therapy
Published
2025-08-29
DOI
https://doi.org/10.1016/j.ymthe.2025.08.031
Primary Topic
Eicosanoids and Hypertension Pharmacology
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Karl Welte, Siarhei Kandabarau, Kateryna Maksymenko, Andrei N. Lupas et al.
Molecular Therapy
Eicosanoids and Hypertension Pharmacology
article

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

Karl Welte, Siarhei Kandabarau, Kateryna Maksymenko, Andrei N. Lupas, Christoph Pollmann, Jérémy Haaf, Maksim Klimiankou, Julia Skokowa, Narges Aghaallaei, Timo Ullrich, Mohammad ElGamacy, Ivan Tesakov, Patrick Müller, Claudia Lengerke, Jacob Piehler, Maya El-Riz, Valeriia Hatskovska, Birte Hernandez-Alvarez, Malte Ritter
article en

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.

Molecular TherapyVol. 33(11)
Max Planck Society (DE), Osnabrück University (DE), Max Planck Institute for Developmental Biology (DE), University Children's Hospital Tübingen (DE), Friedrich Miescher Laboratory (DE), Max Planck Institute for Biology (DE), University of Tübingen (DE)
Deutsche Forschungsgemeinschaft, José Carreras Leukämie-Stiftung, H2020 European Research Council
Openalex Percentile: Top 78%
Eicosanoids and Hypertension Pharmacology
DOIOpen Access PDFOpenAlex
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