%0 Journal Article
%A Ullrich, Timo
%A Pollmann, Christoph
%A Ritter, Malte
%A Haaf, Jérémy
%A Aghaallaei, Narges
%A Tesakov, Ivan
%A Hatskovska, Valeriia
%A El-Riz, Maya
%A Maksymenko, Kateryna
%A Kandabarau, Sergey
%A Klimiankou, Maksim
%A Lengerke, Claudia
%A Welte, Karl
%A Hernandez-Alvarez, Birte
%A Müller, Patrick
%A Lupas, Andrei
%A Piehler, Jacob
%A Skokowa, Julia
%A ElGamacy, Mohammad
%T Tuning of G-CSFR signaling by de novo designed agonists.
%J Molecular therapy
%V 33
%N 11
%@ 1525-0016
%C Amsterdam
%I Elsevier
%M DKFZ-2025-01822
%P 5741-5759
%D 2025
%Z 2025 Nov 5;33(11):5741-5759
%X 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 the 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 open up ways for new therapeutic applications for designed cytokines.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40886048
%R 10.1016/j.ymthe.2025.08.031
%U https://inrepo02.dkfz.de/record/304282