Molecular Therapy: Nucleic Acids (Mar 2025)
Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer
- Vladimira Zlinska,
- Zuzana Feketova,
- Aleksandra Czyrek,
- Julia Chudzian,
- Martina Lenarcic Zivkovic,
- Vlad-Constantin Ursachi,
- Pooja Dudeja,
- Bohumil Fafilek,
- Jan Rynes,
- Gustavo Rico-Llanos,
- Adolf Koudelka,
- Tanaya Roy,
- Martyna Biadun,
- Vendula Raskova,
- Katerina Svozilova,
- Michaela Stroblova,
- Mateusz Krzyscik,
- Kalina Hristova,
- Daniel Krowarsch,
- Silvie Foldynova-Trantirkova,
- Malgorzata Zakrzewska,
- Lukas Trantirek,
- Pavel Krejci
Affiliations
- Vladimira Zlinska
- Central European Institute of Technology, Masaryk University, 625 00 Brno, Czechia; National Centre for Biomolecular Research, Masaryk University, 625 00 Brno, Czechia
- Zuzana Feketova
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia
- Aleksandra Czyrek
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia
- Julia Chudzian
- Department of Protein Engineering, University of Wroclaw, 50-383 Wroclaw, Poland
- Martina Lenarcic Zivkovic
- Slovenian NMR Centre, National Institute of Chemistry, 1000 Ljubljana, Slovenia
- Vlad-Constantin Ursachi
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia
- Pooja Dudeja
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia
- Bohumil Fafilek
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia; Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czechia
- Jan Rynes
- Central European Institute of Technology, Masaryk University, 625 00 Brno, Czechia
- Gustavo Rico-Llanos
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia
- Adolf Koudelka
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia
- Tanaya Roy
- Department of Materials Science and Engineering, Institute for NanoBioTechnology and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA
- Martyna Biadun
- Department of Protein Engineering, University of Wroclaw, 50-383 Wroclaw, Poland
- Vendula Raskova
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia
- Katerina Svozilova
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czechia
- Michaela Stroblova
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia
- Mateusz Krzyscik
- Department of Materials Science and Engineering, Institute for NanoBioTechnology and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA
- Kalina Hristova
- Department of Materials Science and Engineering, Institute for NanoBioTechnology and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA
- Daniel Krowarsch
- Department of Protein Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland
- Silvie Foldynova-Trantirkova
- Central European Institute of Technology, Masaryk University, 625 00 Brno, Czechia
- Malgorzata Zakrzewska
- Department of Protein Engineering, University of Wroclaw, 50-383 Wroclaw, Poland
- Lukas Trantirek
- Central European Institute of Technology, Masaryk University, 625 00 Brno, Czechia; Corresponding author: Lukas Trantirek, Central European Institute of Technology, Masaryk University, Kamenice 753/5, 62500 Brno, Czechia.
- Pavel Krejci
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czechia; Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czechia; Corresponding author: Pavel Krejci, Faculty of Medicine, Masaryk University, Kamenice 753/5, 62500 Brno, Czechia.
- Journal volume & issue
-
Vol. 36,
no. 1
p. 102405
Abstract
Impaired fibroblast growth factor receptor (FGFR) signaling is associated with many human conditions, including growth disorders, degenerative diseases, and cancer. Current FGFR therapeutics are based on chemical inhibitors of FGFR tyrosine kinase activity (TKIs). However, FGFR TKIs are limited in their target specificity as they generally inhibit all FGFRs and other receptor tyrosine kinases. In the search for specific inhibitors of human FGFR1, we identified VZ23, a DNA aptamer that binds to FGFR1b and FGFR1c with a KD of 55 nM and 162 nM, respectively, but not to the other FGFR variants (FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4). In cells, VZ23 inhibited the activation of downstream FGFR1 signaling and FGFR1-mediated regulation of cellular senescence, proliferation, and extracellular matrix homeostasis. Consistent with the specificity toward FGFR1 observed in vitro, VZ23 did not inhibit FGFR2-4 signaling in cells. We show that the VZ23 inhibits FGFR1 signaling in the presence of cognate fibroblast growth factor (FGF) ligands and its inhibitory activity is linked to its capacity to form unusual G-quadruplex structure. Our data suggest that targeting FGFR1 with DNA aptamers could be an effective alternative to TKIs for treating impaired FGFR1 signaling in human craniosynostoses.