A G-quadruplex DNA (GQ) is a non-canonical DNA structure formed by the π−π stacking of multiple G-tetrads held together by Hoogsteen hydrogen-bonding between guanines. DNA sequences with GQ-forming potential are abundant at telomeres and in promoters of oncogenes, making GQs a promising anticancer target. Our research focuses on solving crystal structures of representative GQ DNA and exploring their interactions with the highly selective and well explored porphyrin ligand, N-methylmesoporphyrin IX (NMM). Specifically, we work with VEGF, G4TERT, and Tel26. VEGF is found in the proximal promoter region of the vascular endothelial growth factor gene. Upregulation of this gene promotes growth of cancer cells. G4TERT is found in the promoter region of hHERT gene, which encodes the catalytic domain of human telomerase and promotes cancer cell survival. Tel26 is a G-rich telomeric sequence found in the promoter region of <i>Tetrahymena thermophila</i>. We have also designed a variety of variants of these sequences to increase our chances for successful crystallization. We have performed biophysical characterizations of GQs alone and in complex with NMM using circular dichroism, UV-vis spectroscopy, PAGE gel, Analytical Ultra-centrifugation, and isothermal titration calorimetry. Our data suggest that G4TERT and VEGF form parallel stranded GQ structures and Tel26 forms a hybrid structure; all bind well to NMM (Kd &lt; 1 mM). NMM maintains parallel geometry of GQs or converts hybrid GQs to a parallel conformation and at the same time stabilizing the structures. Crystallization trials of all three GQs alone and in complex with NMM are underway. Our results will explain NMM’s exceptional selectivity toward GQ DNA. Such knowledge is invaluable for improving the design of anticancer therapeutics.

Characterization of G-quadruplex DNA structures and their complexes with N-methylmesoporphyrin IX

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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