Abstract
G-quadruplex- and i-motif-based DNA oligomers are being investigated for their integration into therapeutic and diagnostic micro-assemblies. Examples include quadruplex-forming aptamers as potential anti-HIV agents, and serum-stable quadruplexes as carriers for delivering porphyrins into cancer cells for photodynamic therapy. The i-motifs from C-rich DNA find application in pH-triggered hydrogels that can carry agents like drugs, proteins, and polymers to their targets. The pH-dependent conformational dynamics of i-motifs also make them useful as biosensors for detecting pH changes in cellular microenvironments. Due to these and many other applications, and in an effort to present a compendia of recent uses of quadruplexes and i-motifs, this chapter will concern itself with formation of G-quadruplexes and i-motifs; their physical and chemical properties; the effects of molecular crowding and hydration on their structure and stability; and their application in therapeutics as drug targets, drug-delivery vehicles, and diagnostic tools.
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References
Arnott S, Chandrasekaran R, Marttila CM (1974) Structures for polyinosinic acid and polyguanylic acid. Biochem J 141:537–543
Arola A, Vilar R (2008) Stabilisation of G-quadruplex DNA by small molecules. Curr Top Med Chem 8:1405–1415
Balasubramanian S, Hurley LH, Neidle S (2011) Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 10:261–275
Bates PJ, Laber DA, Miller DM et al (2009) Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol 86:151–164
Bejugam M, Sewitz S, Shirude PS et al (2007) Trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands: small molecule regulation of c-kit oncogene expression. J Am Chem Soc 129:12926–12927
Biffi G, Tannahill D, McCafferty J et al (2013) Quantitative visualization of DNA G-quadruplex structures in human cells. Nat Chem 5:182–186
Blackburn EH (2000) Telomere states and cell fates. Nature 408:53–56
Bock LC, Griffin LC, Latham JA et al (1992) Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 355:564–566
Brooks TA, Kendrick S, Hurley LH (2010) Making sense of G-quadruplex and i-motif functions in oncogene promoters. FEBS J 277:3459–3469
Brown DM, Gray DM, Patrick MH et al (1985) Photochemical demonstration of stacked C · C base pairs in a novel DNA secondary structure. Biochemistry 24:1676–1683
Burge S, Parkinson GN, Hazel P et al (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res 34:5402–5415
Burger AM, Dai F, Schultes CM et al (2005) The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res 65:1489–1496
Campbell NH, Neidle S (2012) G-quadruplexes and metal ions. In: Sigel A, Sigel H, Sigel RK (eds) Interplay between metal ions and nucleic acids. Springer, Netherlands, pp 119–134
Chan SW, Blackburn EH (2002) New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21:553–563
Chen JL, Sperry J, Ip NY et al (2011) Natural products targeting telomere maintenance. Med Chem Commun 2:229–245
Chen C, Li M, Xing Y et al (2012) Study of pH-induced folding and unfolding kinetics of the DNA i-motif by stopped-flow circular dichroism. Langmuir 28:17743–17748
Chen C, Zhou L, Geng J et al (2013) Photosensitizer‐incorporated quadruplex DNA‐gated nanovechicles for light‐triggered. Targeted dual drug delivery to cancer cells. Small. doi:10.1002/smll.201201916:
Cheng E, Xing Y, Chen P et al (2009) A pH‐triggered, fast‐responding DNA hydrogel. Angew Chem 121:7796–7799
Counter CM, Hahn WC, Wei W et al (1998) Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci USA 95:14723–14728
De Lange T (1994) Activation of telomerase in a human tumor. Proc Natl Acad Sci USA 91:2882
Dhakal S, Cui Y, Koirala D et al (2013) Structural and mechanical properties of individual human telomeric G-quadruplexes in molecularly crowded solutions. Nucleic Acids Res 41:3915–3923
Drygin D, Siddiqui-Jain A, O’Brien S et al (2009) Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res 69:7653–7661
Düchler M (2012) G-quadruplexes: targets and tools in anticancer drug design. J Drug Target 20:389–400
Gellert M, Lipsett MN, Davies DR (1962) Helix formation by guanylic acid. Proc Natl Acad Sci USA 48:2013–2018
Gowan SM, Heald R, Stevens MF et al (2001) Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol Pharmacol 60:981–988
Grütter MG, Priestle JP, Rahuel J et al (1990) Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J 9:2361–2365
Guedin A, Gros J, Alberti P et al (2010) How long is too long? Effect of loop size on G-quadruplex stability. Nucleic Acids Res 38:7858–7868
Guittat L, De Cian A, Rosu F et al (2005) Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro. Biochim Biophys Acta 1724:375–384
Han H, Hurley LH (2000) G-quadruplex DNA: a potential target for anti-cancer drug design. Trends Pharmacol Sci 21:136–141
Han H, Hurley LH, Salazar M (1999) A DNA polymerase stop assay for G-quadruplex-interactive compounds. Nucleic Acids Res 27:537–542
Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
Hazel P, Huppert J, Balasubramanian S et al (2004) Loop-length-dependent folding of G-quadruplexes. J Am Chem Soc 126:16405–16415
Hu K, Huang Y, Zhao S et al (2012) Ultrasensitive detection of potassium ions based on target induced DNA conformational switch enhanced fluorescence polarization. Analyst 137:2770–2773
Huang C, Chang H (2008) Aptamer-based fluorescence sensor for rapid detection of potassium ions in urine. Chem Commun 12:1461–1463
Hud NV, Smith FW, Anet FA et al (1996) The selectivity for K versus Na in DNA quadruplexes is dominated by relative free energies of hydration: a thermodynamic analysis by 1H NMR. Biochemistry 35:15383–15390
Hurley LH, Wheelhouse RT, Sun D et al (2000) G-quadruplexes as targets for drug design. Pharmacol Ther 85:141–158
Kan Z, Yao Y, Wang P et al (2006) Molecular crowding induces telomere G‐quadruplex formation under salt‐deficient conditions and enhances its competition with duplex formation. Angew Chem Int Ed 45:1629–1632
Keum J, Bermudez H (2012) DNA-based delivery vehicles: pH-controlled disassembly and cargo release. Chem Commun 48:12118–12120
Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015
Kim M, Gleason-Guzman M, Izbicka E et al (2003) The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures. Cancer Res 63:3247–3256
Kypr J, Kejnovská I, Renčiuk D et al (2009) Circular dichroism and conformational polymorphism of DNA. Nucleic Acids Res 37:1713–1725
Lane AN, Chaires JB, Gray RD et al (2008) Stability and kinetics of G-quadruplex structures. Nucleic Acids Res 36:5482–5515
Langridge R, Rich A (1963) Molecular structure of helical polycytidylic acid. Nature 198:725–728
Li W, Feng L, Ren J et al (2012a) Visual detection of glucose using conformational switch of i‐motif DNA and non‐crosslinking gold nanoparticles. Chem Eur J 18:12637–12642
Li C, Zhu L, Zhu Z et al (2012b) Backbone modification promotes peroxidase activity of G-quadruplex-based DNAzyme. Chem Commun 48:8347–8349
Liu D, Bruckbauer A, Abell C et al (2006) A reversible pH-driven DNA nanoswitch array. J Am Chem Soc 128:2067–2071
Liu C, Huang C, Chang H (2009) Highly selective DNA-based sensor for lead (II) and mercury (II) ions. Anal Chem 81:2383–2387
Longhese MP (2008) DNA damage response at functional and dysfunctional telomeres. Genes Dev 22:125–140
Magbanua E, Zivkovic T, Hansen B et al (2013) d (GGGT) 4 and r (GGGU) 4 are both HIV-1 inhibitors and interleukin-6 receptor aptamers. RNA Biol 10:216–227
Mergny J, Lacroix L (1998) Kinetics and thermodynamics of i-DNA formation: phosphodiester versus modified oligodeoxynucleotides. Nucleic Acids Res 26:4797–4803
Miyoshi D, Sugimoto N (2008) Molecular crowding effects on structure and stability of DNA. Biochimie 90:1040–1051
Miyoshi D, Nakao A, Sugimoto N (2002) Molecular crowding regulates the structural switch of the DNA G-quadruplex. Biochemistry 41:15017–15024
Miyoshi D, Inoue M, Sugimoto N (2006) DNA logic gates based on structural polymorphism of telomere DNA molecules responding to chemical input signals. Angew Chem Int Ed 45:7716–7719
Modi S, Wani AH, Krishnan Y (2006) The PNA–DNA hybrid I-motif: implications for sugar–sugar contacts in i-motif tetramerization. Nucleic Acids Res 34:4354–4363
Modi S, Swetha M, Goswami D et al (2009) A DNA nanomachine that maps spatial and temporal pH changes inside living cells. Nat Nanotechnol 4:325–330
Moorhouse AD, Santos AM, Gunaratnam M et al (2006) Stabilization of G-quadruplex DNA by highly selective ligands via click chemistry. J Am Chem Soc 128:15972–15973
Moyzis RK, Buckingham JM, Cram LS et al (1988) A highly conserved repetitive DNA sequence, (TTAGGG) n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85:6622–6626
Neidle S, Balasubramanian S (2006) Quadruplex nucleic acids. RSC Publishing, London
Neidle S, Parkinson G (2002) Telomere maintenance as a target for anticancer drug discovery. Nat Rev Drug Discov 1:383–393
Neidle S, Read MA (2000) G‐quadruplexes as therapeutic targets. Biopolymers 56:195–208
Rachwal PA, Findlow IS, Werner JM et al (2007) Intramolecular DNA quadruplexes with different arrangements of short and long loops. Nucleic Acids Res 35:4214–4222
Rajendran A, Nakano S, Sugimoto N (2010) Molecular crowding of the cosolutes induces an intramolecular i-motif structure of triplet repeat DNA oligomers at neutral pH. Chem Commun 46:1299–1301
Randazzo A, Esposito V, Ohlenschläger O et al (2004) NMR solution structure of a parallel LNA quadruplex. Nucleic Acids Res 32:3083–3092
Raymond E, Sun D, Chen S et al (1996) Agents that target telomerase and telomeres. Curr Opin Biotechnol 7:583
Read M, Harrison RJ, Romagnoli B et al (2001) Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc Natl Acad Sci USA 98:4844–4849
Risitano A, Fox KR (2004) Influence of loop size on the stability of intramolecular DNA quadruplexes. Nucleic Acids Res 32:2598–2606
Sacks DB (2011) A1C versus glucose testing: a comparison. Diabetes Care 34:518–523
Saretzki G (2003) Telomerase inhibition as cancer therapy. Cancer Lett 194:209–219
Seenisamy J, Bashyam S, Gokhale V et al (2005) Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J Am Chem Soc 127:2944–2959
Sharma NK, Ganesh KN (2005) PNA C–C i-motif: superior stability of PNA TC8 tetraplexes compared to DNA TC8 tetraplexes at low pH. Chem Commun 34:4330–4332
Shieh Y, Yang S, Wei M et al (2010) Aptamer-based tumor-targeted drug delivery for photodynamic therapy. ACS Nano 4:1433–1442
Shum K, Zhou J, Rossi JJ (2013) Nucleic acid aptamers as potential therapeutic and diagnostic agents for lymphoma. J Cancer Ther 4:872–890
Siddiqui-Jain A, Grand CL, Bearss DJ et al (2002) Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci USA 99:11593–11598
Smirnov I, Shafer RH (2000) Effect of loop sequence and size on DNA aptamer stability. Biochemistry 39:1462–1468
Smirnov IV, Shafer RH (2007) Electrostatics dominate quadruplex stability. Biopolymers 85:91–101
Steinert S, Shay JW, Wright WE (2004) Modification of subtelomeric DNA. Mol Cell Biol 24:4571–4580
Sun D, Hurley LH (2009) The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression. J Med Chem 52:2863–2874
Sun C, Wang X, Yang X et al (2013) A label-free electrochemical aptasensor for sensitive thrombin detection in whole blood. Electrochim Acta 106:327–332
Teng Y, Girvan AC, Casson LK et al (2007) AS1411 alters the localization of a complex containing protein arginine methyltransferase 5 and nucleolin. Cancer Res 67:10491–10500
Zhang AYQ, Bugaut A, Balasubramanian S (2011) A Sequence-Independent analysis of the loop length dependence of intramolecular RNA G-quadruplex stability and topology. Biochemistry 50:7251–7258
Zhao Y, Du Z, Li N (2007) Extensive selection for the enrichment of G4 DNA motifs in transcriptional regulatory regions of warm blooded animals. FEBS Lett 581:1951–1956
Zhou J, Zhu X, Lu Y et al (2005) Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines. Oncogene 25:503–511
Zhou J, Wei C, Jia G et al (2010) Formation of i-motif structure at neutral and slightly alkaline pH. Mol Biosyst 6:580–586
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Bhavsar-Jog, Y.P., Reilly, S.M., Wadkins, R.M. (2014). DNA G-Quadruplexes and I-Motifs in Therapeutics and Diagnostics. In: Erdmann, V., Markiewicz, W., Barciszewski, J. (eds) Chemical Biology of Nucleic Acids. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54452-1_24
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DOI: https://doi.org/10.1007/978-3-642-54452-1_24
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