Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer
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 t...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253124002920 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Vladimira Zlinska |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ad06bb25575b42c4981efaaf0a6ec8c5 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-ad06bb25575b42c4981efaaf0a6ec8c52024-12-14T06:30:44ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102405Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamerVladimira Zlinska0Zuzana Feketova1Aleksandra Czyrek2Julia Chudzian3Martina Lenarcic Zivkovic4Vlad-Constantin Ursachi5Pooja Dudeja6Bohumil Fafilek7Jan Rynes8Gustavo Rico-Llanos9Adolf Koudelka10Tanaya Roy11Martyna Biadun12Vendula Raskova13Katerina Svozilova14Michaela Stroblova15Mateusz Krzyscik16Kalina Hristova17Daniel Krowarsch18Silvie Foldynova-Trantirkova19Malgorzata Zakrzewska20Lukas Trantirek21Pavel Krejci22Central European Institute of Technology, Masaryk University, 625 00 Brno, Czechia; National Centre for Biomolecular Research, Masaryk University, 625 00 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, CzechiaDepartment of Protein Engineering, University of Wroclaw, 50-383 Wroclaw, PolandSlovenian NMR Centre, National Institute of Chemistry, 1000 Ljubljana, SloveniaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, CzechiaDepartment 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, CzechiaCentral European Institute of Technology, Masaryk University, 625 00 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, CzechiaDepartment of Materials Science and Engineering, Institute for NanoBioTechnology and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218, USADepartment of Protein Engineering, University of Wroclaw, 50-383 Wroclaw, PolandDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czechia; Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, CzechiaDepartment of Materials Science and Engineering, Institute for NanoBioTechnology and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218, USADepartment of Materials Science and Engineering, Institute for NanoBioTechnology and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218, USADepartment of Protein Biotechnology, University of Wroclaw, 50-383 Wroclaw, PolandCentral European Institute of Technology, Masaryk University, 625 00 Brno, CzechiaDepartment of Protein Engineering, University of Wroclaw, 50-383 Wroclaw, PolandCentral 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.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.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.http://www.sciencedirect.com/science/article/pii/S2162253124002920MT: Oligonucleotides: Therapies and ApplicationsFGFR signalingFGFR1inhibitorDNA aptamerextracellular domain |
| spellingShingle | 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 Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications FGFR signaling FGFR1 inhibitor DNA aptamer extracellular domain |
| title | Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer |
| title_full | Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer |
| title_fullStr | Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer |
| title_full_unstemmed | Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer |
| title_short | Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer |
| title_sort | specific inhibition of fibroblast growth factor receptor 1 signaling by a dna aptamer |
| topic | MT: Oligonucleotides: Therapies and Applications FGFR signaling FGFR1 inhibitor DNA aptamer extracellular domain |
| url | http://www.sciencedirect.com/science/article/pii/S2162253124002920 |
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