G-Quadruplexes as Targets for Drug Design

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Certain DNA sequences have the capability to form DNA secondary structures that have molecular recognition features quite distinct to duplex DNA. In particular, we are interested in a group of four-stranded structures called G-quadruplexes or DNA tetraplexes. Motifs for the formation of G-quadruplexes appear to be rare in the eukaryotic genome but are found in regions of biological significance (e.g., telomeres and promoter regions). We have identified small molecules that target these sequences and affect the rate of formation and unwinding of G- quadruplexes. In this proposal, I describe experiments that will determine the effect of these small molecules on the role that G- quadruplexes play in switch mechanisms in regulatory regions of oncogenes and in stabilizing t-loops in telomeric regions. Other possible roles of G-quadruplexes in recombination and their in vivo existence will also be evaluated. Biophysical methods, including NMR and PAGE, will be used primarily in this study. The specific aims of this proposal are to (1) determine the molecular mechanism that results in the down- regulation of c-myc by G-quadruplex and i-motif-interactive compounds; (2) determine the molecular structure of the t-loop invasion complex and use this as a guide to develop new telomere- interactive compounds; (3) determine the effect of G-quadruplex-interactive compounds on other protein-G-quadruplex complexes, including the topoisomerase I-G-quadruplex DNA; (4) use LM-PCR to probe for the occurrence of G-quadruplex structures in vivo.