A Rationally Designed Azobenzene Photoswitch for DNA G-Quadruplex Regulation in Live Cells
G-quadruplex (G4) DNA structures are in-creasingly acknowledged as promising targets in cancerresearch, and the development of G4-specific stabilizingcompounds may lay a fundamental foundation inprecision medicine for cancer treatment. Here, wepropose a light-responsive G4-binder for precise modu-la...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/386542 |
| Acceso en línea: | http://hdl.handle.net/10261/386542 |
| Access Level: | acceso abierto |
| Palabra clave: | Azobenzene Cancer cells DNA G-quadruplex Photochromism |
| Sumario: | G-quadruplex (G4) DNA structures are in-creasingly acknowledged as promising targets in cancerresearch, and the development of G4-specific stabilizingcompounds may lay a fundamental foundation inprecision medicine for cancer treatment. Here, wepropose a light-responsive G4-binder for precise modu-lation of drug activation, providing dynamic and spatio-temporal control over G4-associated biological proc-esses contributing to cancer cell death. We developed aspecialized fluorinated azobenzene (AB) switchequipped with a quinoline unit and a positively chargedcarboxamide side chain, Q-Azo4F-C, designed fortargeted binding to G4 structures within cells. Biophys-ical studies, combined with molecular dynamics simula-tions, provide insights into the unique coordinationmodes of the photoswitchable ligand in its trans and cisconfigurations when interacting with G4s. The observedvariations in complexation processes between the twoisomeric states in different cancer cell lines manifest inmore than 25-fold reversible cytotoxic activity. Immu-nostaining conducted with the structure-specific G4antibody (BG4), establishes a direct correlation betweencytotoxicity and the varying extent of G4 inductionregulated by the two isoforms. Finally, we demonstratethe photo-driven reversible regulation of G4 structuresin lung cancer cells by Q-Azo4F-C. Our findings high-light the potential of light-responsive G4-binders inadvancing precision cancer therapy through dynamiccontrol of G4-mediated pathways |
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