Selective binding of a bioactive porphyrin-based photosensitizer to the G-quadruplex from the KRAS oncogene promoter

Autor: Marco Caterino, Yana I. Pylina, Olga M. Starseva, Concetta Giancola, Jussara Amato, Andrey V. Kustov, I. S. Khudyaeva, T. R. Usacheva, D. B. Berezin, Dmitrii V. Belykh, Federica D’Aria
Přispěvatelé: Caterino, M., D'Aria, F., Kustov, A. V., Belykh, D. V., Khudyaeva, I. S., Starseva, O. M., Berezin, D. B., Pylina, Y. I., Usacheva, T., Amato, J., Giancola, C.
Rok vydání: 2020
Předmět:
Circular dichroism
Porphyrins
Light
Oligonucleotides
Ligand
02 engineering and technology
Ligands
G-quadruplex
medicine.disease_cause
Proto-Oncogene Mas
Biochemistry
Proto-Oncogene Proteins p21(ras)
HeLa
03 medical and health sciences
chemistry.chemical_compound
Structural Biology
Chlorin
Singlet oxygen generation
medicine
Humans
heterocyclic compounds
Photosensitizer
Promoter Regions
Genetic
Cytotoxicity
Molecular Biology
Photodynamic activity
030304 developmental biology
0303 health sciences
Photosensitizing Agents
biology
Chemistry
Inverted Repeat Sequences
Water
Biological activity
General Medicine
021001 nanoscience & nanotechnology
biology.organism_classification
Combinatorial chemistry
Porphyrin
G-Quadruplexes
Molecular Docking Simulation
Biophysic
Photochemotherapy
Solubility
KRAS
0210 nano-technology
HeLa Cells
Zdroj: International Journal of Biological Macromolecules. 145:244-251
ISSN: 0141-8130
DOI: 10.1016/j.ijbiomac.2019.12.152
Popis: Background The G-quadruplex-forming sequence within the KRAS proto-oncogene P1 promoter is a promising target for anticancer therapy. Porphyrin derivatives are among the most rewarding G-quadruplex binders. They can also behave as photosensitizers. Methods Three water-soluble, positively charged porphyrin-like compounds were synthesized and tested for their interaction with the KRAS G-quadruplex by circular dichroism, fluorescence, and molecular docking calculations. For a comparison of ligands binding affinity and selectivity, TMPyP4 was taken as a reference. Results One out of the three tested compounds proved biological activity and selectivity for G-quadruplex over duplex DNA. It also showed to discriminate between different G-quadruplex topologies, with a preference for the parallel over antiparallel conformation. Molecular docking studies suggested a preferential binding to the 3′-end of the KRAS G-quadruplex driven through π-π stacking interactions. Biological assays also revealed a good photodynamic-induced cytotoxicity on HeLa cells. Conclusions The reported results show that these porphyrin-like compounds could actually give the basis for the development of G-quadruplex ligands with effective photodynamic-induced cytotoxicity on cancer cells. General significance The possibility of obtaining photosensitizers with improved physico-chemical features and able to selectively target G-quadruplexes is a very interesting perspective to develop new therapeutic agents.
Databáze: OpenAIRE
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