The selectivity of N-methyl mesoporphyrin IX (NMM) for G-quadruplexes (GQs) is long known, however its ability to stabilize and bind GQs has not been investigated in detail.  Through the use of circular dichroism, UV-visible spectroscopy, and FRET melting assay we have shown that NMM stabilizes human telomeric DNA dAGGG(TTAGGG)3 (Tel22), is selective for its parallel conformation, and causes isomerization of Tel22 into a structure with increased parallel component. The N--methyl group is integral for selectivity and stabilization. NMM binds to Tel22 with 1:1 stoichiometry and ~1.0�105 M-1 binding constant.  Additionally, NMM stabilizes a variety of other biologically relevant G-rich sequences such as oncogene promoters.    Crystallographic studies of NMM-Tel22 complex as well as investigations into the mechanism of NMM-induced Tel22 isomerization are underway.  Results, taken together, indicate that NMM presents an interesting platform towards developing a promising cancer drug that acts via structural transformation and subsequent stabilization of specific GQ targets.

Molecular details of interactions between human telomeric DNA and quadruplex specific ligand, N-methylmesoporphyrin IX

244th National Meeting (2012)

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