G quadruplexes as targets for drug design pdf

Guanosine grich dna and rna sequences can adopt a defined secondary structure, the gquadruplex, which consists of multiple stacked gtetrads. Located in key functional regions of genomes, gquadruplexes play important regulatory roles in transcription, replication and translation processes. These gquadruplexes are an active target of drug discovery. Gquadruplex nucleic acid, which is formed by selfassembly of guaninerich nucleic acid sequences, has recently been considered as an attractive target for anticancer drug design. The dna gquadruplexes formed in the promoter region of oncogene have been. Gquadruplexes have been proposed as tar gets for drug design 1115. Request pdf gquadruplexes as targets for drug design g quadruplexes are a family of secondary dna structures formed in the presence of monovalent cations that consist of fourstranded. Metalloorganic gquadruplex ligands in anticancer drug design. Within a gtetrad, four guanine bases are arranged in a square plane with hoogsteen hydrogen bonding, instead of the watsoncrick hydrogen bonding of bdna figure 1a, b. Secondary dna structures as molecular targets for cancer. Dna quadruplexes, also known as gquadruplex structures, comprise stacked tetrads, each of which arises from the planar association of four guanines in a cyclic hoogsteen hydrogenbonding arrangement. As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles. Recent evidences suggest their intimate involvement in important biological processes such as.

Gquadruplex structures were studied using different experimental techniques, such as molecular. Each gtetrad has four gs arranged in a planar configuration and held together by hydrogen bonding. The nuclease hypersensitivity element iii1 nhe iii1 of the cmyc promoter can form transcriptionally active and silenced forms, and the formation of dna gquadruplex structures has been shown to be critical for cmyc transcriptional silencing. A potential target for anticancer drug design in addition to the familiar duplex dna, certain dna sequences can fold into. Hurley lh1, wheelhouse rt, sun d, kerwin sm, salazar m, fedoroff oy. Telomeres have received much attention in this regard since they can fold into several distinct intramolecular gquadruplexes, leading to the rational design and development of gquadruplex. Particularly, gquadruplexmediated transcription regulation of. Smallmoleculebased selfassembled ligands for gquadruplex. Structurebased approaches targeting oncogene promoter gquadruplexes 3 been widely employed, the use of computational analysis for identifying gquadruplex ligands has been comparatively less explored ma et al.

These sequences in telomeric dna and some oncogenes have. For instance, stabilization of gquadruplex structures within the promoter of myc, kit, or kras resulted in the downregulation of the corresponding. Hurley lh, wheelhouse rt, sun d et al 2000 gquadruplexes as targets for drug design. In molecular biology, gquadruplex secondary structures g4 are formed in nucleic acids by sequences that are rich in guanine. Gquadruplexes as targets for drug design request pdf. Although the putative g quadruplexforming sequences present an opportunity for a range of drug targets, they also represent a potential problem of drug selectivity. However, designing drugs to target g quadruplexes in the human genome is by no means an easy task, as the drugs need to specifically target the intended g quadruplexes from among the vast number. Inhibiting telomerase by stabilizing g quadruplexes and inducing g.

The study of gquadruplexes g4s in a cellular context has demonstrated links between these nucleic acid secondary structures, gene expression, and dna replication. Affinityselected bicyclic peptide gquadruplex ligands. Design and synthesis of fluoroquinophenoxazines that. Other than in telomeres, gquadruplexes may form at additional locations in the human genome, including gene promoters and untranslated regions. Considerable circumstantial evidence suggests that these structures can exist in vivo in specific regions of the genome including the telomeric ends of chromosomes and oncogene regulatory regions. Gquadruplex structures are formed by stacked guanine tetrads gtetrads figure 1. Unimolecular parallelstranded gquadruplex structures are found to be prevalent in gene promoters. Dna gquadruplex and its potential as anticancer drug target. Gquadruplexes are nonwatsoncrick fourstranded nucleic acid structures.

The basic unit of a gquadruplex is a gquartet, a planar motif generated from four guanine. Gquadruplexes are the most recent secondary dna structures that are being considered as targets for drug design. Gquadruplex dna as a target for drug design request pdf. In this chapter, we first describe the general structure of gquadruplexes and their involvement in transcriptional. Embryonal tumors include a heterogeneous group of highly malignant neoplasms that primarily affect infants and children and are characterized by a high rate of mortality and treatmentrelated morbidity, hence improved therapies are clearly needed. Gquadruplexes are secondary structures that may form within guaninerich nucleic acid sequences. The electrochemical and atomic force microscopy characterization of gquadruplexes is presented.

Gquadruplex dna targeted metal complexes acting as. Guaninerich dna sequences can form planar fourstranded structures via hoogsteen hydrogen bonds. Clinical relevance of targeting gquadruplex dna riou et al. The existence of chaperone proteins that facilitate their for. Recent evidence points toward their existence in vivo and their implication in various biological processes.

Quadruplex structure transition and formation lige ren college of chemistry and molecular sciences, wuhan university, hongshan, luo jia shan, hubei, wuhan 430072, p. Characterization of highly conserved gquadruplex motifs. Find, read and cite all the research you need on researchgate. Gquadruplexes have become valid targets for new anticancer drugs in the past few decades.

Design and synthesis of fluoroquinophenoxazines that interact. G quadruplexes are a family of secondary dna structures formed in the presence of monovalent cations that consist of fourstranded structures in which hoogsteen basepairing stabilizes g tetrad structures. Structurebased approaches targeting oncogene promoter g. Gquadruplexes are fourstranded dna structures that are overrepresented in gene promoter regions and are viewed as emerging therapeutic. Taken together, these studies highlight the vast potential for the biological functions of gquadruplexes in vivo. The first proof of the guanine g selfassociation called gquadruplex was reported by davies. Gquadruplexes and associated gene targets for drug design. Ligands that bind to the g4 structure therefore present an excellent opportunity for influencing gene expression through the targeting of a nucleic acid structure rather than sequence. Nucleic acids may form noncanonical tetraplex secondary structures called gquadruplexes.

Gquadruplexes are a family of secondary dna structures formed in the presence of monovalent cations that consist of fourstranded structures in which hoogsteen basepairing stabilizes gtetrad structures. Clearly, more research will be needed to rigorously validate rna gquadruplexes as drug targets for therapeutics applications and explore how selective ligands can be for a given rna gquadruplex. Few of the possible topologies have been observed to date by nmr or crystallography, either as native structures or as smallmolecule complexes, although some therapeutically relevant startingpoints for structurebased drug design are now available, for human telomeric 811,12, c. Part of the upcoming challenge will be to better understand the mechanistic effects and selectivity factors on endogenous mrnas in the all complexity. The existence of chaperone proteins that facilitate their for mation 2527, gquadruplex binding. Gquadruplexes have been found in eukaryotic and prokaryotic genomes, including viruses. In this article, the structures of these unusual fourstranded dna molecules, the roles that these secondary structures might play in cells, and finally the way in which. Gquadruplexes are essential for understand ing their biological functions, as well as for the rational design of small. The progress was due to understanding the structural features of gquadruplexes. Gquadruplex nucleic acids as therapeutic targets europe.

The tetrameric arrangement of guanosine has been known since. Request pdf gquadruplexes as targets for drug design gquadruplexes are a family of secondary dna structures formed in the presence of monovalent cations that consist of fourstranded. Therapeutically useful drugs that target dna are thought to interact primarily with duplex dna, although their real targets might be more accurately regarded as proteindna structures such as topoisomerasedna complexes. The gquadruplexes formed in rna are involved in many biological process including telomere elongation, transcription regulate, premrna splicing and translation. Quadruplex ligands selectively suppress the growth of tumor cells by indirectly attenuating telomerase activity or inhibiting oncogene expression. They are helical in shape and contain guanine tetrads that can form from one, two or four strands. Superhelical torsional stress may be an important determinant of these structures in cells lo. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Dna gquadruplexes the dna mainly exist in its typical double helix b dna conformation proposed by watson and crick, however it can also adopt other secondary structures, such as gquadruplexes. Gquadruplex structures in the human genome as novel.

Gquadruplexes as targets for drug design sciencedirect. These ligands were shown to selectively exert an antiproliferative. Several gquadruplex forming motifs have been reported to be highly conserved in the regulatory regions of the genome of different organisms and. The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of. Over the past two decades, small molecules have been developed to specifically and selectively target these structures in order to dissect mechanisms they have been linked to. Since potential therapeutic significance had been discovered for quadruplex secondary structures of nucleic acids, many compounds stabilizing these targets were identified. The dna g quadruplexes formed in the promoter region of oncogene have been. These structures are proposed to exist in vivo, although direct confirmatory evidence is lacking.

As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of smallligand binding to these structures should be. Gquadruplexes are special secondary structures adopted in guanine grich dna sequences that are often present in biologically important regions. Gquadruplexes as potential therapeutic targets for. Because telomere maintenance mechanisms and the transcriptional regulation of oncogene expression are important targets for drug design. Gquadruplexes g4s are noncanonical secondary structures that fold within guanine g rich strands of regulatory genomic regions. Request pdf on jan 1, 2000, lh hurley and others published gquadruplexes and associated gene targets for drug design. Several compounds that target these structures have shown promising anticancer activity in tumor xenograft models and some of them have entered. Emerging targets for the structurebased design of potential anticancer and antiviral therapies.