G-quadruplex dna as a target for drug design pdf

Division of medicinalchemistry and institute for cellular and molecular biology, the universityof texas, austin, tx 78712, usa keywords. In molecular biology, gquadruplex secondary structures g4 are formed in nucleic acids by sequences that are rich in guanine. Such a structure might be important for telomere biology 514,1619 and a good target for drug design 514,1921. Such a structure might be important for telomere biology 514, 1619 and a good target for drug design 514, 1921. Dynamic combinatorial chemistry dcc has emerged as a promising strategy for templatedriven selection of highaffinity ligands for biological targets from equilibrating combinatorial libraries. We aim at spearheading your drugligand discovery efforts for gquadruplex. These 3,6,9trisubstituted acridine inhibitors are predicted to interact selectively with the human dna quadruplex. Therapeutically useful drugs that target dna are thought to interact primarily with duplex dna, although their real targets might be more accurately regarded as protein dna structures such as topoisomerase dna complexes 75. Sheet3 sheet2 sheet1 authors year title journal page volume issue pubmed id abstract impact factor snippet link date doi ge, x.

It is a unique, comprehensive and wellorganized database of gquadruplex ligands. Recent advances in targeting the telomeric gquadruplex. Binding properties of human telomeric quadruplex multimers. Four guanine bases can associate through hoogsteen hydrogen bonding to form a square planar structure called a guanine tetrad, and two or more guanine tetrads. Because of their unique structural features and possible extensive cellular functions, gquadruplexes constitute a very attractive target for drug design 12. Gquadruplex dna targeted metal complexes acting as. In most of these studies, the target structures were the single quadruplex units formed by short human dna telomeric sequences typically 21e26 nt. Gquadruplex dna, a noncanonical secondary nucleic acid structure formed by guaninerich genomic sequences 1,2, has been viewed as an emerging therapeutic target in oncology due to its potential roles in oncogene transcriptional regulation, dna replication and telomere stability 5,6. One such example is the fourstranded gquadruplex dna. Fluorescence techniques for nucleic acids chemical biology. The binding of the drug confers significant stability to the gquadruplex complex, as does the presence of the potassium ions.

A potential target for anticancer drug design in addition to the familiar duplex dna, certain dna sequences can fold into. Smallmoleculebased selfassembled ligands for gquadruplex. Over the past two decades, particular interest has been paid on this structure and the. They are helical in shape and contain guanine tetrads that can form from one, two or four strands. However, most recent results from the encode project indicate that only 3% of human genome is expressed in protein and that rna and dna may form noncanonical secondary structures that are functionally important.

Guaninerich dna sequences able to form qdna structures. Gquadruplexes as targets for drug design sciencedirect. However, only a few examples using disulfideexchangebased dcc are reported for nucleic acid targets. Targets, sequences and topologies target sequence 5 to. Hurley in addition to the familiar duplex dna, certain dna sequences can fold into secondary structures that are four. Gquadruplexes are dna secondary structures formed by guaninerich sequences, for example, within gene promoters where they may contribute to transcriptional activity.

Gquadruplex dna as a potential drug target many currently used chemotherapeu. The basic unit of a gquadruplex is a gquartet, a planar motif generated from four guanine residues pairing together through hoogsteen like hydrogen bonds. The synthesis of oligomers containing two or three acridine units linked through 2aminoethylglycine using solidphase methodology is described. Binding to several dna structures was studied by competitive dialysis, which showed a clear affinity for dna sequences that form gquadruplexes and parallel triplexes. A mrnaresponsive gquadruplexbased drug release system. These results indicate that it is possible to design functional gquadruplexes for any desired target sequence. Gquadruplexes are essential for understand ing their biological functions, as well as for the rational design of small. The dna g quadruplexes formed in the promoter region of oncogene have been. Several groups have been engaged in the design and development of gquadruplexinteractive compounds, and as a result several lead compounds have been identified see below. Subsequent studies on cell viability showed that these compounds are not cytotoxic. Structural basis for telomeric gquadruplex targeting by.

A selective gquadruplex dnastabilizing ligand based on a cyclic naphthalene diimide derivative. The ability to thermally stabilize human telomeric dna as a fourstranded gquadruplex structure by developing selective small molecule compounds is a therapeutic path to. Dynamic generation of gquadruplex dna ligands by target. 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. In the past decade, several research groups have been focused on the design of new ligands trying to optimize the interactions between these small molecules and the gquadruplex motif. Despite a recent explosion of interest in gquadruplex dna, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. One of the considered strategies is to induce different dna lesions and to target speci. The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of. The telomerase enzyme is a potential therapeutic target in many human cancers. G quadruplexes as promising targets for anticancer drug design. They are without a doubt one of the most intriguing yet controversial sma. In addition, gquadruplex structures are associated with human telomeres and. Recent work has revealed that stabilizing gquadruplexes in telomeric dna inhibits telomerase activity, providing impetus for the development of gquartetinteracting drugs, while gquartetcontaining oligonucleotides have been recognized as a potent class of aptamers effective against stat3 and other transcription factors implicated in oncogenesis, proving these guaninequartets to be a vital. The latter strategy has been used to elucidate complex na structures, which include the hammerhead ribozyme 23 and the human telometric gquadruplex 27.

Analysis of small molecules designed to target gquadruplex dna structures tajanena romell, jan jamroskovic, erik chorell abstract the gquadruplex dna structure is quickly coming into the spotlight in many fields of chemistry and biology. The dna gquadruplexes formed in the promoter region of oncogene have been. Compounds that stabilize gquadruplex structures in telomeric dna block telomerase activity and may be potentially valuable as antitumor drugs. Because telomere maintenance mechanisms and the transcriptional regulation of oncogene expression are important targets for drug design.

Furthermore, small molecules that stabilize gquadruplex structures have been found to be effective telomerase inhibitors and, then, the use of drugs to target gquadruplexes is emerging as a promising way to. Here, we would also exhibit some typical drug delivery designs. In addition to the familiar duplex dna, certain dna sequences can fold into secondary structures that are fourstranded. Research open access on and offtarget effects of telomere. Pdf the gquadruplex is one of the most important dna secondary. Targetdirected approaches for screening small molecules. Quadruplex structures and their interaction diversity. The dna gquadruplex binding pentacyclic acridinium salt rhps4 1 has many pharmacological attributes of an ideal telomeretargeting agent but has undesirable offtarget liabilities. The progress was due to understanding the structural features of gquadruplexes. Gquadruplex dna as a target for drug design volume.

Rna molecules have a variety of cellular functions that can drive disease pathologies. We provide a variety of data inquiry methods for you to efficiently retrieve, analyze, and design gquadruplex ligands. Gquadruplexes gtetrads or g4dna are nucleic acid sequences that are rich in guanine and are capable of forming a fourstranded structure. Herein, we have demonstrated that goldcoated magnetic nanoparticleconjugated dna targets can be. Dna gquadruplex and its potential as anticancer drug target. Realtime monitoring of dna gquadruplexes in living cells. A mrnaresponsive gquadruplexbased drug release system hidenobu yaku 1, takashi murashima 2. Gquadruplex dna as a target for drug design request pdf. A potential target for anticancer drug design in addition to the familiar duplex dna, certain dna sequences can fold into secondary structures that are four. A series of potent inhibitors has been designed by computer modeling, which exploit the unique structural features of quadruplex dna. A thorough characterization of the binding interaction between a drug and its molecular target is fundamental to successfully lead drug design. Dna is widely recognized as a doublehelical structure with a crucial role in genetic information storage.

You are at the portal of the gquadruplex ligands database g4ldb. Gquadruplex inhibitors agonists modulators antagonists. We computed a quantitatively wellcharacterized free. Pds is a pyridostatin compound which shows potent gquadruplexstabilization and has been widely used to study gquadruplex functions and gquadruplexinduced dna damage 176, 210, 211, 212, 233. In addition, gquadruplex dna was also shown to be potential cancer therapeutics. We demonstrate that this characterization is also possible using the recently developed method of funnelmetadynamics fm, here applied to investigate the binding of berberine to dna gquadruplex.

Ligand binding to telomeric gquadruplex dna investigated. Gquadruplex dna as a target for drug design bentham science. Gquadruplex structures in the human genome as novel. These gquadruplexes are an active target of drug discovery. G quadruplex dna, drug design, tetrahymena, metal ion binding, structural diversity, telomerase inhibition, ethidium bromide, diaminoanthraquinones. Gquadruplexes are the most recent secondary dna structures that are being considered as targets for drug design. Pdf gquadruplex dna as a target for drug design sean. Quadruplex ligands selectively suppress the growth of tumor cells by indirectly attenuating telomerase activity or inhibiting oncogene expression. Rnadirected drug design that can selectively target gquadruplex rna. Gquadruplexes have been shown to in hibit telomerase activity and drugs that stabilize these tetraplexes could interfere with telomere replication. The proximal promoter of vegfr2 contains a gquadruplex, which has been suggested to interact with small molecules that inhibit vegfr2 expression and thereby tumor angiogenesis. Gquadruplex drug interaction department of chemistry. Gquadruplex dna is involved in a variety of cellular activities, such as dna replication and dna transcription 4,5. Since potential therapeutic significance had been discovered for quadruplex secondary structures of nucleic acids, many compounds stabilizing these targets were identified.