Current Topics in Medicinal Chemistry - Volume 15, Issue 19, 2015

Chromosomes in human cells are protected by telomeres. Telomere shortens during each round of cell division because of the DNA end-replication problem. Cancer cells maintain telomere length homeostasis by either telomerase or/and the alternative lengthening of telomere (ALT) mechanism to sustain their division potential. Telomeric DNA tends to form G-quadruplex preferentially at the extreme 3’ end. This unique feature prevents the 3’ end from being used as a substrate of telomerase and as a primer in the ALT. Therefore, stabilizing telomere G-quadruplex is expected to inhibit both pathways and limit the proliferation of cancer cells. Based on a mathematical modeling and experimental results, this mini-review proposes a hypothesis that the formation of G-quadruplex in telomere may constitute a significant contribution to the incomplete end-replication of telomere DNA by preventing the priming of DNA synthesis near the 3’ end during telomere replication. According to this, stabilization of telomere G-quadruplex by chemical ligand may promise to accelerate telomere shortening in proliferating cells.

Roles of RNA on transcriptional and post-transcriptional regulations have raised more attention since the new era of genomics. One of the secondary structures of RNA, the RNA Gquadruplex structure, is demonstrated a relatively stable existence in human tumor cells, virus, or other species relating to diseases. G-quadruplexes are special secondary structures formed by G-rich DNA and RNA sequences that fold into a four-stranded conformation. The G-quadruplexes formed in RNA are involved in many biological process including telomere elongation, transcription regulate, pre-mRNA splicing and translation. In this review, we will give a brief introduction to the structures of RNA G-quadruplexes, the biological roles and the potential to be as drug targets.

The G-quadruplex structure is a non-canonical secondary DNA motif that is built from planar tetrads of guanine residues stabilized by Hoogsteen-type hydrogen bonding. Bioinformatics studies indicate that sequences rich in guanine that are able to form G-quadruplexes are widely distributed throughout the human genome, particularly in telomere and promoter regions of genes. G-quadruplex sequences found in the promoters of human oncogenes, such as k-ras, c-myc and bcl-2 have attracted particular attention as molecular targets for therapeutic intervention due to their potential capability to regulate gene expression at the transcriptional level. Moreover, the G-quadruplex structure has been associated with a number of human diseases arising from defective telomeric maintenance. Despite intensive research in this area, however, the actual function of G-quadruplexes in vivo has not yet been fully understood. Therefore, significant efforts have been devoted to the discovery of specific probes for visualizing and distinguishing G-quadruplex structures from other nucleic acid molecules likely to be found in biological environments. This review summarizes recent studies in the development of G-quadruplex probes over the past three years, with a particular emphasize on the detection and imaging of G-quadruplex structures within living cells. Furthermore, the detection and biological relevance of RNA G-quadruplexes is discussed.

Compelling evidence suggests that formation of guanine-quadruplex (G4) can protect the integrity of chromosome ends in eukaryotes, and regulate the activity of some gene promoters. In addition, G4 may be a novel therapeutic target. Thus, a number of ligands have been synthesized to stabilize G4. However, skepticism lingers over the existence of G4 in cells, as well as its biological function. The molecule 3,6-bis(1-methyl-4-vinylpyridium) carbazole diiodide (BMVC) can be used not only as a fluorescent probe to map endogenous and exogenous G4 in live cells, but also as therapeutic agent that arrests cancer growth by inhibiting telomerase activity and regulating gene expression. Thus, the fluorescence of a G4 anti-cancer agent is an invaluable tool to detect G4 in cells, investigate ligand-G4 interaction in live cells, examine the biological function of G4, and guide the development of new fluorescent anti-cancer agents.

G-quadruplexes are four-stranded DNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Accumulating studies have revealed that Gquadruplex structures are formed in vivo and play important roles in biological processes such as DNA replication, transcription, recombination, epigenetic regulation, meiosis, antigenic variation, and maintenance of telomeres stability. Mounting evidence indicates that a variety of proteins are capable of binding selectively and tightly to G-quadruplex and play essential roles in G-quadruplex-mediated regulation processes. Some of these proteins promote the formation or/and stabilization of Gquadruplex, while some other proteins act to unwind G-quadruplex preferentially. From a drug discovery perspective, many of these G-quadruplex binding proteins and/or their complexes with G-quadruplexes are potential drug targets. Here, we present a general summary of reported G-quadruplex binding proteins and their biological functions, with focus on those of medicinal research significance. We elaborated the possibility for some of these G-quadruplex binding proteins and their complexes with G-quadruplexes as potential drug targets.

The G-quadruplex is one of the most important DNA secondary structures and has elicited widespread interest in this field of scientific research. As Gquadruplex studies have progressed, its significant roles in a variety of biological process have been revealed, including telomerase activity, genome stability, DNA replication, and oncogene expression. In addition to its biological functions, as a special DNA quadruplex structure, it also has potential for other important applications like asymmetric catalysis, probing for important biomarkers, acting as a vehicle for drug delivery, or as a structural regulator for some nanostructure designs. Here, we discuss its application to aspects of biological target detection and drug delivery. Its utility in biological target detection mainly results from its special DNAzyme activity. We would summarize some typical systems, utilizing G-quadruplex as signal readout unit, for various target detection, such as SNP, miRNAs, ions, transcription factors and so on. On the other hand, its use in drug delivery always relies on probes’ structural change, as the switch of drug release. Here, we would also exhibit some typical drug delivery designs.