Hurley, L. H. (1980). DNA as a mobile target for drug action. Pharmacy International, 1(9), 178-181.
Hurley, L. H., Kang, H., Cui, Y., Yin, H., Scheid, A., Kong, D., & Mao, H. (2016). A pharmacological chaperone molecule induces cell death by restoring tertiary DNA structures in mutant hTERT promoters. Nature Medicine.
Weisman-Shomer, P., Cohen, E., Hershco, I., Khateb, S., Wolfovitz-Barchad, O., Hurley, L. H., & Fry, M. (2003). The cationic porphyrin TMPyP4 destabilizes the tetraplex form of the fragile X syndrome expanded sequence d(CGG)n. Nucleic Acids Research, 31(14), 3963-3970.
PMID: 12853612;PMCID: PMC165968;Abstract:
Fragile X syndrome, the most common cause of inherited mental retardation, is instigated by dynamic expansion of a d(CGG) trinucleotide repeat in the 5′-untranslated region of the first exon of the FMR1 gene, resulting in its silencing. The expanded d(CGG)n tract readily folds into hairpin and tetraplex structures which may contribute to the blocking of FMR1 transcription. In this work, we report that the cationic porphyrin 5,10,15,20-tetra(N-methyl-4-pyridyl)porphin (TMPyP4) effectively destabilizes in vitro the G′2 bimolecular tetraplex structure of d(CGG)n while it stabilizes the G′2 tetraplex: form of the telomeric sequence d(TTAGGG)2. Similarly to TMPyP4, the hnRNP-related protein CBF-A also destabilizes G′2 tetrahelical d(CGG)n while binding and stabilizing tetraplex telomeric DNA. We report that relative to each agent individually, successive incubation of G′2 d(CGG)n with TMPyP4 followed by exposure to CBF-A results in a nearly additive extent of disruption of this tetraplex form of the repeat sequence. Our observations open up the prospect of unfolding secondary structures of the expanded FMR1 d(CGG)n tract of fragile X cells by their exposure to low molecular size drugs or to proteins such as TMPyP4 or CBF-A.
Rangan, A., Fedoroff, O. Y., & Hurley, L. H. (2001). Induction of Duplex to G-quadruplex Transition in the c-myc Promoter Region by a Small Molecule. Journal of Biological Chemistry, 276(7), 4640-4646.
PMID: 11035006;Abstract:
A major control element of the human c-myc oncogene is the nuclease-hypersensitive purine/pyrimidine-rich sequence. This double-stranded DNA fragment, corresponding to the 27-base pair segment in the nuclease-hypersensitive element of the c-myc promoter region, forms a stable Watson-Crick double helix under physiological conditions. However, this duplex DNA can be effectively converted to G-quadruplex DNA by a small molecular weight ligand. Both intermolecular and intramolecular G-quadruplex forms can be induced by this ligand. Similar transitional changes are also observed with the duplex telomeric sequence from the Oxytricha species. These results provide additional support to the idea that G-quadruplex structures may play structural roles in vivo and also provide insight into novel methodologies for rational drug design. These structurally altered DNA elements might serve as regulatory signals in gene expression or in telomere dynamics and hence are promising targets for drug action.
Bearss, D. J., Hurley, L. H., & D., D. (2000). Telomere maintenance mechanisms as a target for drug development. Oncogene, 19(56), 6632-6641.
PMID: 11426649;Abstract:
The shortening of the telomeric DNA sequences at the ends of chromosomes is thought to play a critical role in regulating the lifespan of human cells. Since all dividing cells are subject to the loss of telomeric sequences, cells with long proliferative lifespans need mechanisms to maintain telomere integrity. It appears that the activation of the enzyme telomerase is the major mechanism by which these cells maintain their telomeres. The proposal that a critical step in the process of the malignant transformation of cells is the upregulation of expression of telomerase has made this enzyme a potentially useful prognostic and diagnostic marker for cancer, as well as a new target for therapeutic intervention for the treatment of patients with cancer. It is now clear that simply inhibiting telomerase may not result in the anticancer effects that were originally hypothesized. While telomerase may not be the universal target for cancer therapy, we certainly believe that targeting the telomere maintenance mechanisms will be important in future research aimed toward a successful strategy for curing cancer.
