G-quadruplexes as targets for drug design pdf

Selective targeting of gquadruplex using furanbased cyclic. Thus, the dynamics of folding and unfolding of these structures and the effect that g quadruplexinteractive compounds have on these processes will be important aspects of the development of g quadruplexes as targets for drug design. The existence of chaperone proteins that facilitate their for mation 2527, gquadruplex binding. The development of small molecules that specifically bind to a particular dna secondary structure may improve cancerspecific tar. Guaninerich dna sequences can fold into fourstranded, noncanonical secondary structures called gquadruplexes g4s. The existence of chaperone proteins that facilitate their for.

Inhibiting telomerase by stabilizing g quadruplexes and inducing g. Recent studies have demonstrated that small molecules can facilitate the formation of, and stabilize, g quadruplexes. Pdf dna gquadruplexes, telomerespecific proteins and. We have synthesized a pair of furanbased cyclic homooligopeptides, ligand 1 and ligand 2, to specifically target g quadruplexes. We have shown by cd spectroscopy and uv melting that these ligands can effectively induce g quadruplex structures in the g rich 22mer cmyc dna sequence and further stabilize the structure. We have identified small molecules that target these sequences and affect the rate of formation and unwinding of g. Enzymes as targets for drug design is a collection of scientific discussions related to enzyme inhibitors that show the many facets of the drug discovery process from the basic sciences through clinical applications.

Specifically targeting mixedtype dimeric gquadruplexes. The development of a ligand that is capable of distinguishing among the wide variety of gquadruplex structures and targeting telomeres to treat cancer is particularly challenging. Pdf the gquadruplex is one of the most important dna secondary. Metalloorganic gquadruplex ligands in anticancer drug design. 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. Design and synthesis of fluoroquinophenoxazines that interact. Because telomere maintenance mechanisms and the transcriptional regulation of oncogene expression are important targets for drug design. Todays goals become oriented with maestro user interface and some popular tools set up and run a selfdocking job with glide to validate our target model dock a known binder to our target structure learn how to use docking analysis tools empower you to explore additional tools for virtual screening, addressing receptor flexibility, and other tools that will help to. 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. 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. The gquadruplexes are evolutionary conserved, highly stable secondary structures, and shown to orchestrate throughout the genome such as telomere, promoter of. We have identified small molecules that target these sequences and affect the rate of formation and unwinding of g quadruplexes. We then discuss the development of g quadruplex interacting small molecules as potential drug candidates.

Owing to the significant roles that both telomeres and myc play in cancer cell biology, gquadruplexes have been viewed as emerging therapeutic targets in oncology and as tools for novel anticancer drug design. Here, we would also exhibit some typical drug delivery designs. Design and synthesis of fluoroquinophenoxazines that. Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Compound 1a with the shortest polyether linker showed the highest affinity k a 10 8 m. The dna g quadruplexes formed in the promoter region of oncogene have been. Rna is also considered a potential target for anticancer drugs, and lately considerable research e. Topics include the biogenesis of phosphatidylinositol glycosyl membrane proteins, structure and catalytic function of adpribose polymerase adprt, and modulation of the. Putative hiv and siv gquadruplex sequences in coding and. They rationalize that targeting the gquadruplexes in hiv offers an attractive therapeutic target, which would be of particular use in the development of novel antiviral therapies. These sequences in telomeric dna and some oncogenes have. Gquadruplex dna as a potential drug target many currently used chemotherapeutic agents bind to dna nonspecifically e.

Sequence effects in singlebase loops for quadruplexes. Gquadruplexes g4s are noncanonical secondary structures that fold within guanine g rich strands of regulatory genomic regions. One such target are g quadruplex dna motifs, which occur throughout the human genome and are involved in a myriad of biological processes, including telomere maintenance, replication and transcription. 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.

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. Gquadruplexes are guanine rich secondary structures of dna. Since potential therapeutic significance had been discovered for quadruplex secondary structures of nucleic acids, many compounds stabilizing these targets were identified. The progress was due to understanding the structural features of gquadruplexes. Dec 17, 2014 a therapeutic effect demonstrated in vivo supports the idea that g quadruplexes are promising for the development of targeted anticancer drugs. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Dna g quadruplexes 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 g quadruplexes. G quadruplex structures were studied using different experimental techniques, such as molecular. Emerging targets for the structurebased design of potential anticancer and antiviral therapies g quadruplexes g4s are noncanonical secondary structures that fold within guanine g rich strands of regulatory genomic regions. Each gtetrad has four gs arranged in a planar configuration and held together by hydrogen bonding. Part of the upcoming challenge will be to better understand the mechanistic effects and selectivity factors on endogenous mrnas in the all complexity.

Conclusion drug designing is a multidisciplinary, complex, costly and intellect intensive process. Structurebased approaches targeting oncogene promoter g quadruplexes 3 been widely employed, the use of computational analysis for identifying g quadruplex ligands has been comparatively less explored ma et al. Gquadruplexes g4s are frequently formed in the promoter regions of oncogenes, regulate their expression, and are considered as promising drug targets for anticancer therapy. This is especially true in terms of gene sequencing, and to date more than 9 thousand genomic sequences of hiv isolates have been sequenced and analyzed. G quadruplexes are special secondary structures adopted in guanine g rich dna sequences that are often present in biologically important regions. Pdf gquadruplex dna as a target for drug design sean. The g quadruplexes formed in rna are involved in many biological process including telomere elongation, transcription regulate, premrna splicing and translation. Interaction patterns between drugsmall molecules and double stranded dna. Dna gquadruplexes have recently emerged as a new class of novel molecular targets for anticancer drugs. The tetrameric arrangement of guanosine has been known since. The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of. Recent evidences suggest their intimate involvement in important biological processes such as. Visualization of parallel gquadruplexes in cells with a.

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. Each g tetrad has four gs arranged in a planar configuration and held together by hydrogen bonding. Gquadruplex dna targeted metal complexes acting as potential. Smallmoleculebased selfassembled ligands for gquadruplex. Several such sequences were found in various coding and noncoding. Apr 30, 2018 evidence of the broader role g quadruplexes play in information metabolism has also grown tremendously in the past decades giving us potential therapeutic targets for cancer and similar diseases. Gquadruplex structures in the human genome as novel.

Emerging targets for the structurebased design of potential anticancer and antiviral therapies. Gquadruplexes as potential therapeutic targets for. In this study, a series of dna sequences, which have the potential to form g quadruplex structures, is analyzed. In this chapter, we first describe the general structure of g quadruplexes 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. When 2 or more guanine tetrads stack they form a gquadruplex, which is further stabilised by the presence of a cation, usually potassium. However, several issues still need to be addressed both at chemical and biological level before gquadruplexinteracting molecules will turn out into effective therapeutic agents. G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Gquadruplexes as potential therapeutic targets for embryonal. The first proof of the guanine g selfassociation called g quadruplex was reported by davies. The analysis of grich regions can provide researchers with a path to find specific targets that could be of interest for specific types of virus. Three polyethertethered berberine dimers 1ac were studied for their binding affinity, selectivity and thermal stabilization towards human telomeric dimeric quadruplex dna g2t1. Each tetrad is composed of four g residues that are linked by the sugarphosphate backbone and connected through. Smeller semmelweis university, department of biophysics and radiation biology, budapest, tuzolto utca 3747, hungary keywords. Recent progress on structural studies of the biologically relevant gquadruplexes formed in human telomeres and in the promoter regions of human oncogenes will be discussed, as well as recent advances in the design and development of g. G quadruplexes can inhibit normal cell function, and in healthy cells, are easily and readily unwound by helicase.

Role of loop residues and cations on the formation and. Because of their unique structural features and possible extensive cellular functions, gquadruplexes constitute a very attractive target for drug design 12. However, in cancer cells that have mutated helicase these complexes cannot be unwound. Gquadruplex nucleic acids as a target for pancreatic. Gquadruplexes g4s are unique fourstranded nucleic acid secondary structures formed by grich nucleic acid sequences which are prevalent in gene promoter and telomere regions and deemed to play essential roles in many biological and pathological processes. Quadruplexspecific molecules can serve as suitable drugs in cancer therapy. Drug design thomas funkhouser princeton university cs597a, fall 2005 introduction drugs molecules that can be introduced to change biological activity slide courtesy of bill welsh introduction drug targets enzyme inhibitors receptor agonists or antagonists ion channels blockers transporter update inhibitors dna blockers. Quadruplex ligands selectively suppress the growth of tumor cells by indirectly attenuating telomerase activity or inhibiting oncogene expression. Pieces of evidence indicate that targeting gquadruplexes may represent an innovative and fascinating approach for the therapeutic management of the neoplastic disease. Guanosine grich dna and rna sequences can adopt a defined secondary structure, the gquadruplex, which consists of multiple stacked gtetrads. Guaninerich dna sequences can form planar fourstranded structures via hoogsteen hydrogen bonds.

Gquadruplexes with 4n 1 guanines in the gtetrad core. These gquadruplexes are an active target of drug discovery. The possible role of g quadruplexinteractive compounds as pharmacologically important molecules is explored in this article. Gquadruplexes as targets for drug design sciencedirect. Superhelical torsional stress may be an important determinant of these structures in cells lo. A the building blocks of gquadruplexes are gquartets that arise from the association of four guanines into a cyclic arrangement stabilized by hoogsten hydrogen bonding n1n6 and n2n7. 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.

G quadruplexes are fourstranded dna structures that are overrepresented in gene promoter regions and are viewed as emerging therapeutic targets in oncology, as transcriptional repression of oncogenes through stabilization of these structures could be a novel anticancer strategy. We use this to highlight how fundamental research has contributed to identifying biological functions of g quadruplexes and their potential as therapeutic targets. The future of gquadruplexes as targets for drug design gquadruplexes are the most recent secondary dna structures that are being considered as targets for drug design. Structurebased approaches targeting oncogene promoter g. The first class does not properly represent a novel g4 architecture, but rather includes higherorder structures generated by the crosstalk of two or more independent g4s that are adjacent along the primary sequence.

High pressure infrared spectroscopy studies on g quadruplexes. Synthetic lethality can also be achieved chemically by combination of drug like molecules targeting distinct but cooperative pathways. Secondary dna structures as molecular targets for cancer. In this work, we focus on two new peculiar classes of g4s that recently emerged as interesting molecular targets for drug design. The hiv virus is one of the most studied viruses in the world. Each tetrad is composed of four g residues that are linked by the sugarphosphate backbone and connected through hoogsteentype hydrogen. Telomeres and telomerase have been subjects to a tremendousattention from scientists and oncologists during the past 5 years. They are helical in shape and contain guanine tetrads that can form from one, two or four strands. Gquadruplex dna targeted metal complexes acting as. Hurley lh1, wheelhouse rt, sun d, kerwin sm, salazar m, fedoroff oy. G quadruplexes as targets for drug design author links open overlay panel laurence h. Drug mode of binding covalent non covalent alkylating agents irreversible and leads to complete inhibition of dna processes and subsequent cell death. G quadruplexes, key proteins dna topoisomerase, telomerase, cdk kinase associ. This interest has been motivated by the potential of telomerase asa tumor marker for the diagnosis and the prognosis of.

G quadruplexes have become valid targets for new anticancer drugs in the past few decades. Gquadruplexes and their regulatory roles in biology. Gquadruplexes are essential for understand ing their biological functions, as well as for the rational design of small. Furthermore, the key interactions that guanine makes have been used for their application as electrochemical biosensors and development of nanoscale. In molecular biology, gquadruplex secondary structures g4 are formed in nucleic acids by sequences that are rich in guanine. Although attentions to g4s have been paid for nearly 40 years, g4 selectivity and its topology discrimination in cells is still pending. Compounds that can stabilize the intramolecular dna gquadruplexes formed in the human telomeric sequence have been shown to inhibit the activity of telomerase and telomere maintenance, thus the telomeric dna gquadruplex has been considered as an attractive target for. Gquadruplexes form in vitro in dna or rna sequences containing tracts of three to four guanine. Motifs for the formation of gquadruplexes appear to be rare in the eukaryotic genome but are found in regions of biological significance e. Guanosine g rich dna and rna sequences can adopt a defined secondary structure, the g quadruplex, which consists of multiple stacked g tetrads.

Several compounds that target these structures have shown promising anticancer activity in tumor xenograft models and some of them have. Apr 24, 2007 quaternary ammonium zinc phthalocyanine. Gquadruplexes as targets for drug design request pdf. G quadruplexes have been proposed as tar gets for drug design 1115. Four guanine bases can associate through hoogsteen hydrogen bonding to form a square planar structure, known as a guanine tetrad. Gquadruplexes as targets for drug design university of. 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. Quadruplex structure transition and formation lige ren college of chemistry and molecular sciences, wuhan university, hongshan, luo jia shan, hubei, wuhan 430072, p. Emerging role of gquadruplex dna as target in anticancer. High pressure infrared spectroscopy studies on g quadruplexes j.