Title
Selective binding of a bioactive porphyrin-based photosensitizer to the G-quadruplex from the KRAS oncogene promoter
Author
Marco Caterino, Federica D'Aria, Andrey V. Kustov, Dmitrii V. Belykh, Irina S. Khudyaeva, Olga M. Starseva, Dmitriy B. Berezin, Yana I. Pylina, Tatiana Usacheva, Jussara Amato, Concetta Giancola
Year
2020
Journal
International Journal of Biological Macromolecules
Abstract
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. 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. 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. 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.
Instrument
J-815, FP-8300
Keywords
Circular dichroism, DNA structure, Ligand binding, Thermal stability, Thermodynamics, G-quadruplex structure, Fluorescence, FRET, Biochemistry