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From Nucleic Acids Sequences to Molecular Medicine pp 85–120Cite as

Oligonucleotide Conjugates: Rationale, Synthesis, and Applications

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Part of the book series: RNA Technologies ((RNATECHN))

Abstract

Synthetic oligonucleotides can cause specific inhibition of gene expression by a variety of mechanisms (e.g., antigene, antisense, siRNA). Such oligonucleotides can also cause catalytic cleavage of the target sequence (e.g., ribozyme, DNAzyme) and selectively bind to the target molecules (e.g., aptamers). However, oligonucleotides possess unfavorable pharmacokinetic and pharmacodynamic properties, like extremely short plasma half-life due to the degradation by nucleases, low cellular uptake, and poor target specificity. These unfavorable properties can be improved by either incorporating structural modifications in oligonucleotide or by conjugating (covalently linking) molecules with relevant biological properties (e.g., peptides and proteins, carbohydrates, antibodies, enzymes, polymers, drugs, fluorophores) to oligonucleotide. The conjugate design usually aims to improve the poor pharmacokinetic and pharmacodynamic properties of the unmodified oligonucleotide and, in some cases, to impart new properties to the oligonucleotide. Over the years, a very large number of diverse oligonucleotide conjugates have been developed and evaluated for diagnostic, therapeutic, and nanotechnology-based applications. The aim of this chapter is to describe the underlying reasons and challenges in oligonucleotide conjugate design, provide an overview of chemical approaches available for their synthesis, and highlight some of their recent applications.

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Abbreviations

AMD:

Age-related macular degeneration

COC:

Carbohydrate–oligonucleotide conjugate

CMV:

Cytomegalovirus

CPG:

Controlled pore glass

CPP:

Cell-penetrating peptide

DCC:

Dicyclohexyl carbodiimide

Dde:

1-(4,4-Dimethyl-2,6-dioxacyclohexylidene)ethyl

DMT:

4,4′-Dimethoxy trityl

DNA:

Deoxyribonucleic acid

DTPA:

Dithiol phosphoramidite

DTT:

Dithiothreitol

EDC:

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide

FISH:

Fluorescence in situ hybridization

FO:

Fluorescent oligonucleotide

HBTU:

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HNA:

Hexitol nucleic acid

HOBT:

1-Hydroxybenzotriazole

HPLC:

High-performance liquid chromatography

LCAA:

Long-chain alkyl amino

LNA:

Locked nucleic acid

LOC:

Lipid-oligonucleotide conjugate

MCOC:

Metal complex–oligonucleotide conjugate

MMT:

4-Monomethoxy trityl

NHS:

N-Hydroxysuccinimidyl ester

NOC:

Nanoparticle–oligonucleotide conjugate

ON:

Oligonucleotide

PEG:

Poly(ethylene glycol)

PNA:

Peptide nucleic acid

POC:

Peptide–oligonucleotide conjugate

QCMS:

Quartz crystal microbalance

QD:

Quantum dots

RES:

Reticuloendothelial system

RNA:

Ribonucleic acid

SAM:

Self-assembled monolayer

SERS:

Surface enhanced Raman scattering

shRNA:

Small hairpin ribonucleic acid

siRNA:

Small interfering ribonucleic acid

SMPT:

N-Succinimidylocarbonyl-methyl-(2-pyridyldithio) toluene

SNALP:

Stable nucleic acid lipid particle

SPDP:

N-Succinimidyl 3-(2-pyridyldithio) propionate

SPR:

Surface plasmon resonance

TCEP:

Tris(2-carboxyethyl) phosphine

TOF-SIMS:

Time-of-flight secondary ion mass spectrometry

Tr:

Trityl

VEGF:

Vascular endothelial growth factor

References

  • Aiba Y, Sumaoka J, Komiyama M (2011) Artificial DNA cutters for DNA manipulation and genome engineering. Chem Soc Rev 40:5657–5668

    Article  PubMed  CAS  Google Scholar 

  • Akerman ME, Chan WC, Laakkonen P et al (2002) Nanocrystal targeting in vivo. Proc Natl Acad Sci USA 99:12617–12621

    Article  PubMed  CAS  Google Scholar 

  • Asseline U (2006) Development and applications of fluorescent oligonucleotides. Curr Org Chem 10:491–518

    Article  CAS  Google Scholar 

  • Avino A, Ocampo SM, Lucas R et al (2011) Synthesis and in vitro inhibition properties of siRNA conjugates carrying glucose and galactose with different presentations. Mol Divers 15:751–757

    Article  PubMed  CAS  Google Scholar 

  • Bandy TJ, Brewer A, Burns JR et al (2011) DNA as supramolecular scaffold for functional molecules: progress in DNA nanotechnology. Chem Soc Rev 40:138–148

    Article  PubMed  CAS  Google Scholar 

  • Bano F, Fruk L, Sanavio B et al (2009) Toward multiprotein nanoarrays using nanografting and DNA directed immobilization of proteins. Nano Lett 9:2614–2618

    Article  PubMed  CAS  Google Scholar 

  • Beaucage SL (2001) Strategies in the preparation of DNA oligonucleotide arrays for diagnostic applications. Curr Med Chem 8:1213–1244

    Article  PubMed  CAS  Google Scholar 

  • Berezhna SY, Supekova L, Supek F et al (2006) siRNA in human cells selectively localizes to target RNA sites. Proc Natl Acad Sci USA 103:7682–7687

    Article  PubMed  CAS  Google Scholar 

  • Boersma AJ, Megens RP, Feringa BL et al (2010) DNA-based asymmetric catalysis. Chem Soc Rev 39:2083–2092

    Article  PubMed  CAS  Google Scholar 

  • Bonora GM, Ballico M, Campaner P et al (2003) Synthesis of oligonucleotide-peptide PEG-conjugated: the EGG (oligonucleotide)-chicken (peptide) dilemma? Nucleosides Nucleotides Nucleic Acids 22:1255–1257

    Article  PubMed  CAS  Google Scholar 

  • Bouchard PR, Hutabarat RM, Thompson KM (2010) Discovery and development of therapeutic aptamers. Annu Rev Pharmacol Toxicol 50:237–257

    Article  PubMed  CAS  Google Scholar 

  • Bouillon C, Meyer A, Vidal S et al (2006) Microwave assisted “click” chemistry for the synthesis of multiple labeled-carbohydrate oligonucleotides on solid support. J Org Chem 71:4700–4702

    Article  PubMed  CAS  Google Scholar 

  • Charles I, Xue L, Arya DP (2002) Synthesis of aminoglycoside-DNA conjugates. Bioorg Med Chem Lett 12:1259–1262

    Article  PubMed  CAS  Google Scholar 

  • Chiu YL, Ali A, Chu CY et al (2004) Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem Biol 11(8):1165–1175

    Article  PubMed  CAS  Google Scholar 

  • Corey DR (2007) RNA learns from antisense. Nat Chem Biol 3:8–11

    Article  PubMed  CAS  Google Scholar 

  • Crooke ST (1998) Vitravene—another piece in the mosaic. Antisense Nucleic Acid Drug Dev 8(4):vii–viii

    Article  PubMed  CAS  Google Scholar 

  • Cunningham JJ, Crocker LS, Leone A (2011) Tackling the challenges of nucleic acid delivery: progress and new approaches. Drug Dev Deliv 11:36–40

    CAS  Google Scholar 

  • Da Ros T, Spalluto G, Prato M et al (2005) Oligonucleotides and oligonucleotide conjugates: a new approach for cancer treatment. Curr Med Chem 12:71–88

    Article  PubMed  Google Scholar 

  • Dausse E, Da Rocha GS, Toulme JJ (2009) Aptamers: a new class of oligonucleotides in the drug discovery pipeline? Curr Opin Pharmacol 9:602–607

    Article  PubMed  CAS  Google Scholar 

  • Davis ME, Zuckerman JE, Choi CH et al (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464:1067–1070

    Article  PubMed  CAS  Google Scholar 

  • Dey S, Sheppard TL (2001) Ketone-DNA: a versatile postsynthetic DNA decoration platform. Org Lett 3:3983–3986

    Article  PubMed  CAS  Google Scholar 

  • Dorsett Y, Tuschl T (2004) siRNAs: applications in functional genomics and potential as therapeutics. Nat Rev Drug Discov 3:318–329

    Article  PubMed  CAS  Google Scholar 

  • Duncan B, Kim C, Rotello VM (2010) Gold nanoparticle platforms as drug and biomacromolecule delivery systems. J Control Release 148:122–127

    Article  PubMed  CAS  Google Scholar 

  • Edupuganti OP, Singh Y, Defrancq E et al (2004) New strategy for the synthesis of 3′,5′-bifunctionalized oligonucleotide conjugates through sequential formation of chemoselective oxime bonds. Chem Eur J 10:5988–5995

    Article  PubMed  CAS  Google Scholar 

  • El-Sagheer AH, Cheong VV, Brown T (2011) Rapid chemical ligation of oligonucleotides by the Diels-Alder reaction. Org Biomol Chem 9:232–235

    Article  PubMed  CAS  Google Scholar 

  • Elbashir SM, Harborth J, Lendeckel W et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498

    Article  PubMed  CAS  Google Scholar 

  • Ellington AD, Szostak JW (1990) In vitro selection of RNA molecules that bind specific ligands. Nature 346:818–822

    Article  PubMed  CAS  Google Scholar 

  • Fire A, Xu S, Montgomery MK et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  PubMed  CAS  Google Scholar 

  • Forget D, Boturyn D, Defrancq E et al (2001) Highly efficient synthesis of peptide-oligonucleotide conjugates: chemoselective oxime and thiazolidine formation. Chem Eur J 7:3976–3984

    Article  PubMed  CAS  Google Scholar 

  • Fritzsche W, Taton TA (2003) Metal nanoparticles as labels for heterogeneous, chip-based DNA detection. Nanotechnology 14:R63–R73

    Article  PubMed  CAS  Google Scholar 

  • Gait MJ (2003) Peptide-mediated cellular delivery of antisense oligonucleotides and their analogues. Cell Mol Life Sci 60:844–853

    PubMed  CAS  Google Scholar 

  • Ghosh P, Han G, De M et al (2008) Gold nanoparticles in delivery applications. Adv Drug Deliv Rev 60:1307–1315

    Article  PubMed  CAS  Google Scholar 

  • Ghosh S, Defrancq E (2010) Metal-complex/DNA conjugates: a versatile building block for DNA nanoarrays. Chem Eur J 16:12780–12787

    Article  PubMed  CAS  Google Scholar 

  • Gilbert JC, DeFeo-Fraulini T, Hutabarat RM et al (2007) First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation 116:2678–2686

    Article  PubMed  CAS  Google Scholar 

  • Goncalves MS (2009) Fluorescent labeling of biomolecules with organic probes. Chem Rev 109:190–212

    Article  PubMed  CAS  Google Scholar 

  • Goodchild J (1990) Conjugates of oligonucleotides and modified oligonucleotides: a review of their synthesis and properties. Bioconjug Chem 1:165–187

    Article  PubMed  CAS  Google Scholar 

  • Graham D, Enright A (2006) Cycloadditions as a method for oligonucleotide conjugation. Curr Org Synth 3:175–213

    Article  Google Scholar 

  • Gramlich PM, Wirges CT, Manetto A et al (2008) Postsynthetic DNA modification through the copper-catalyzed azide-alkyne cycloaddition reaction. Angew Chem Int Ed 47:8350–8358

    Article  CAS  Google Scholar 

  • Harney AS, Lee J, Manus LM et al (2009) Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate. Proc Natl Acad Sci USA 106:13667–13672

    Article  PubMed  CAS  Google Scholar 

  • Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2:214–221

    Article  PubMed  CAS  Google Scholar 

  • Hedley D, Ogilvie L, Springer C (2007) Carboxypeptidase-G2-based gene-directed enzyme-prodrug therapy: a new weapon in the GDEPT armoury. Nat Rev Cancer 7:870–879

    Article  PubMed  CAS  Google Scholar 

  • Higgins D, Rodriguez R, Milley R et al (2006) Modulation of immunogenicity and allergenicity by controlling the number of immunostimulatory oligonucleotides linked to Amb a 1. J Allergy Clin Immunol 118:504–510

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann S, Hoos J, Klussmann S, Vonhoff S (2011) RNA aptamers and spiegelmers: synthesis, purification, and post-synthetic PEG conjugation. Curr Protoc Nucleic Acid Chem 46:1–30, Chapter 4:Unit 4

    Google Scholar 

  • Howard KA (2009) Delivery of RNA interference therapeutics using polycation-based nanoparticles. Adv Drug Deliv Rev 61:710–720

    Article  PubMed  CAS  Google Scholar 

  • Jiang Q, Xiao N, Shi P et al (2007) Design of artificial metallonucleases with oxidative mechanism. Coord Chem Rev 251:1951–1972

    Article  CAS  Google Scholar 

  • Jones D (2011) The long march of antisense. Nat Rev Drug Discov 10:401–402

    Article  PubMed  CAS  Google Scholar 

  • Juliano R, Alam MR, Dixit V et al (2008) Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res 36:4158–4171

    Article  PubMed  CAS  Google Scholar 

  • Kachalova AV, Stetsenko DA, Romanova EA et al (2002) A new and efficient method for synthesis of 5′-conjugates of oligonucleotides through amide bond formation on solid phase. Helv Chim Acta 85:2409–2416

    Article  CAS  Google Scholar 

  • Karhunen U, Jaakkola L, Wang Q et al (2010) Luminescence switching by hybridization-directed mixed lanthanide complex formation. Anal Chem 82:751–754

    Article  PubMed  CAS  Google Scholar 

  • Krutzfeldt J, Rajewsky N, Braich R et al (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438:685–689

    Article  PubMed  CAS  Google Scholar 

  • Kurreck J (2003) Antisense technologies. Improvement through novel chemical modifications. Eur J Biochem 270:1628–1644

    Article  PubMed  CAS  Google Scholar 

  • Le Gac S, Rickling S, Gerbaux S et al (2009) A photoreactive ruthenium(II) complex tethered to a guanine-containing oligonucleotide: a biomolecular tool that behaves as a “Seppuku molecule”. Angew Chem Int Ed 48:1122–1125

    Article  CAS  Google Scholar 

  • Lim YC, Kouzani AZ, Duan W (2010) Aptasensors: a review. J Biomed Nanotechnol 6:93–105

    Article  PubMed  CAS  Google Scholar 

  • Lonnberg H (2009) Solid-phase synthesis of oligonucleotide conjugates useful for delivery and targeting of potential nucleic acid therapeutics. Bioconjug Chem 20:1065–1094

    Article  PubMed  CAS  Google Scholar 

  • Lonnberg T, Aiba Y, Hamano Y et al (2010) Oxidation of an oligonucleotide-bound Ce(III)/multiphosphonate complex for site-selective DNA scission. Chem Eur J 16:855–859

    PubMed  Google Scholar 

  • Lonnberg T, Suzuki Y, Komiyama M (2008) Prompt site-selective DNA hydrolysis by Ce(IV)-EDTA using oligonucleotide multiphosphonate conjugates. Org Biomol Chem 6:3580–3587

    Article  PubMed  CAS  Google Scholar 

  • Lundquist JJ, Toone EJ (2002) The cluster glycoside effect. Chem Rev 102:555–578

    Article  PubMed  CAS  Google Scholar 

  • Manoharan M (2002) Oligonucleotide conjugates as potential antisense drugs with improved uptake, biodistribution, targeted delivery, and mechanism of action. Antisense Nucleic Acid Drug Dev 12:103–128

    Article  PubMed  CAS  Google Scholar 

  • Marlin F, Simon P, Saison-Behmoaras T et al (2010) Delivery of oligonucleotides and analogues: the oligonucleotide conjugate-based approach. Chembiochem 11:1493–1500

    Article  PubMed  CAS  Google Scholar 

  • Megger DA, Guerra CF, Hoffmann J et al (2011) Contiguous metal-mediated base pairs comprising two Ag(I) ions. Chem Eur J 17:6533–6544

    Article  PubMed  CAS  Google Scholar 

  • Moschos SA, Jones SW, Perry MM et al (2007) Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem 18:1450–1459

    Article  PubMed  CAS  Google Scholar 

  • Muratovska A, Eccles MR (2004) Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett 558:63–68

    Article  PubMed  CAS  Google Scholar 

  • Ng EW, Shima DT, Calias P et al (2006) Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5:123–132

    Article  PubMed  CAS  Google Scholar 

  • Niemeyer CM, Boldt L, Ceyhan B et al (1999) DNA-directed immobilization: efficient, reversible, and site-selective surface binding of proteins by means of covalent DNA-streptavidin conjugates. Anal Biochem 268:54–63

    Article  PubMed  CAS  Google Scholar 

  • Niemeyer CM, Ceyhan B, Hazarika P (2003) Oligofunctional DNA-gold nanoparticle conjugates. Angew Chem Int Ed 42:5766–5770

    Article  CAS  Google Scholar 

  • Nishina K, Unno T, Uno Y et al (2008) Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol. Mol Ther 16:734–740

    Article  PubMed  CAS  Google Scholar 

  • O’Neill MA, Barton JK (2005) Sequence-dependent DNA dynamics: the regulator of DNA-mediated charge transport. In: Wagenknecht HA (ed) Charge transfer in DNA: from mechanism to application. Wiley-VCH, Germany, pp 27–75

    Google Scholar 

  • Ocampo SM, Albericio F, Fernandez I et al (2005) A straightforward synthesis of 5′-peptide oligonucleotide conjugates using N(alpha)-fmoc-protected amino acids. Org Lett 7:4349–4352

    Article  PubMed  CAS  Google Scholar 

  • Ohrt T, Merkle D, Birkenfeld K et al (2006) In situ fluorescence analysis demonstrates active siRNA exclusion from the nucleus by Exportin 5. Nucleic Acids Res 34:1369–1380

    Article  PubMed  CAS  Google Scholar 

  • Oishi M, Nagasaki Y, Itaka K et al (2005) Lactosylated poly(ethylene glycol)-siRNA conjugate through acid-labile beta-thiopropionate linkage to construct pH-sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells. J Am Chem Soc 127:1624–1625

    Article  PubMed  CAS  Google Scholar 

  • Opalinska JB, Gewirtz AM (2002) Nucleic-acid therapeutics: basic principles and recent applications. Nat Rev Drug Discov 1:503–514

    Article  PubMed  CAS  Google Scholar 

  • Pack DW, Hoffman AS, Pun S et al (2005) Design and development of polymers for gene delivery. Nat Rev Drug Discov 4:581–593

    Article  PubMed  CAS  Google Scholar 

  • Park S, Sugiyama H (2010) DNA-based hybrid for asymmetric organic synthesis. Angew Chem Int Ed 49:3870–3878

    Article  CAS  Google Scholar 

  • Paroo Z, Corey DR (2004) Challenges for RNAi in vivo. Trends Biotechnol 22:390–394

    Article  PubMed  CAS  Google Scholar 

  • Paterson BM, Roberts BE, Kuff EL (1977) Structural gene identification and mapping by DNA-mRNA hybrid-arrested cell-free translation. Proc Natl Acad Sci USA 74:4370–4374

    Article  PubMed  CAS  Google Scholar 

  • Rayburn ER, Zhang R (2008) Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible? Drug Discov Today 13:513–521

    Article  PubMed  CAS  Google Scholar 

  • Rosemeyer H (2005) Nucleolipids: natural occurrence, synthesis, molecular recognition, and supramolecular assemblies as potential precursors of life and bioorganic materials. Chem Biodivers 2:977–1063

    Article  PubMed  CAS  Google Scholar 

  • Rostovtsev VV, Green LG, Fokin VV et al (2002) A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew Chem Int Ed 41:2596–2599

    Article  CAS  Google Scholar 

  • Rozema DB, Lewis DL, Wakefield DH et al (2007) Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci USA 104:12982–12987

    Article  PubMed  CAS  Google Scholar 

  • Ryou SM, Kim S, Jang HH et al (2010) Delivery of shRNA using gold nanoparticle-DNA oligonucleotide conjugates as a universal carrier. Biochem Biophys Res Commun 398:542–546

    Article  PubMed  CAS  Google Scholar 

  • Ryou SM, Park M, Kim JM et al (2011) Inhibition of xenograft tumor growth in mice by gold nanoparticle-assisted delivery of short hairpin RNAs against Mcl-1 L. J Biotechnol 156:89–94

    Article  PubMed  CAS  Google Scholar 

  • Sassolas A, Blum LJ, Leca-Bouvier BD (2011) Optical detection systems using immobilized aptamers. Biosens Bioelectron 26:3725–3736

    Article  CAS  Google Scholar 

  • Sayyed SG, Hagele H, Kulkarni OP et al (2009) Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes. Diabetologia 52:2445–2454

    Article  PubMed  CAS  Google Scholar 

  • Schilling CI, Jung N, Biskup M et al (2011) Bioconjugation via azide–Staudinger ligation: an overview. Chem Soc Rev 40:4840–4871

    Article  PubMed  CAS  Google Scholar 

  • Schoch J, Wiessler M, Jaschke A (2010) Post-synthetic modification of DNA by inverse-electron-demand Diels-Alder reaction. J Am Chem Soc 132:8846–8847

    Article  PubMed  CAS  Google Scholar 

  • Semple SC, Akinc A, Chen J et al (2010) Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 28:172–176

    Article  PubMed  CAS  Google Scholar 

  • Seo TS, Li Z, Ruparel H et al (2003) Click chemistry to construct fluorescent oligonucleotides for DNA sequencing. J Org Chem 68:609–612

    Article  PubMed  CAS  Google Scholar 

  • Silverman SK (2010) DNA as a versatile chemical component for catalysis, encoding and stereocontrol. Angew Chem Int Ed 49:7180–7201

    Article  CAS  Google Scholar 

  • Singh N, Agrawal A, Leung AK et al (2010a) Effect of nanoparticle conjugation on gene silencing by RNA interference. J Am Chem Soc 132:8241–8243

    Article  PubMed  CAS  Google Scholar 

  • Singh Y, Defrancq E, Dumy P (2004) New method to prepare peptide-oligonucleotide conjugates through glyoxylic oxime formation. J Org Chem 69:8544–8546

    Article  PubMed  CAS  Google Scholar 

  • Singh Y, Murat P, Defrancq E (2010b) Recent developments in oligonucleotide conjugation. Chem Soc Rev 39:2054–2070

    Article  PubMed  CAS  Google Scholar 

  • Singh Y, Spinelli N, Defrancq E (2008) Chemical strategies for oligonucleotide conjugate synthesis. Curr Org Chem 12:263–290

    Article  CAS  Google Scholar 

  • Smith D, Holley AC, McCormick CL (2011) RAFT-synthesized copolymers and conjugates designed for therapeutic delivery of SiRNA. Polym Chem 2:1428–1441

    Article  CAS  Google Scholar 

  • Song S, Wang L, Li J et al (2008) Aptamer-based biosensors. Trends Anal Chem 27:108–117

    Article  CAS  Google Scholar 

  • Spinelli N, Edupuganti OP, Defrancq E et al (2007) New solid support for the synthesis of 3′-oligonucleotide conjugates through glyoxylic oxime bond formation. Org Lett 9:219–222

    Article  PubMed  CAS  Google Scholar 

  • Stephenson ML, Zamecnik PC (1978) Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci USA 75:285–288

    Article  PubMed  CAS  Google Scholar 

  • Stetsenko DA, Gait MJ (2000) Efficient conjugation of peptides to oligonucleotides by “native ligation”. J Org Chem 65:4900–4908

    Article  PubMed  CAS  Google Scholar 

  • Tombelli S, Mascini M (2009) Aptamers as molecular tools for bioanalytical methods. Curr Opin Mol Ther 11:179–188

    PubMed  CAS  Google Scholar 

  • Truffert JC, Asseline U, Brack A et al (1996) Synthesis, purification, and characterization of two peptide oligonucleotide conjugates as potential artificial nuclease. Tetrahedron 52:3005–3016

    Article  CAS  Google Scholar 

  • Tuccitto N, Giamblanco N, Ghosh S et al (2011) Controlled density patterning of tolylterpyridine-tagged oligonucleotides. Langmuir 27:8595–8599

    Article  PubMed  CAS  Google Scholar 

  • Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505–510

    Article  PubMed  CAS  Google Scholar 

  • Tung CH, Stein S (2000) Preparation and applications of peptide-oligonucleotide conjugates. Bioconjug Chem 11:605–618

    Article  PubMed  CAS  Google Scholar 

  • Wang K, Tang Z, Yang CJ et al (2009) Molecular engineering of DNA: molecular beacons. Angew Chem Int Ed 48:856–870

    Article  CAS  Google Scholar 

  • Weisbrod SH, Marx A (2008) Novel strategies for the site-specific covalent labelling of nucleic acids. Chem Commun 44:5675–5685

    Article  CAS  Google Scholar 

  • Whitehead KA, Langer R, Anderson DG (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8:129–138

    Article  PubMed  CAS  Google Scholar 

  • Yang M, Jin H, Chen J et al (2011) Efficient cytosolic delivery of siRNA using HDL-mimicking nanoparticles. Small 7:568–573

    Article  PubMed  CAS  Google Scholar 

  • Yuan X, Naguib S, Wu Z (2011) Recent advances of SiRNA delivery by nanoparticles. Exp Opin Drug Deliv 8:521–536

    Article  CAS  Google Scholar 

  • Zatsepin TS, Oretskaya TS (2004) Synthesis and applications of oligonucleotide-carbohydrate conjugates. Chem Biodivers 1:1401–1417

    Article  PubMed  CAS  Google Scholar 

  • Zatsepin TS, Romanova EA, Stetsenko DA et al (2003) Synthesis of 2′-modified oligonucleotides containing aldehyde or ethylenediamine groups. Nucleosides Nucleotides Nucleic Acids 22:1383–1385

    Article  PubMed  CAS  Google Scholar 

  • Zatsepin TS, Stetsenko DA, Arzumanov AA et al (2002) Synthesis of peptide-oligonucleotide conjugates with single and multiple peptides attached to 2′-aldehydes through thiazolidine, oxime, and hydrazine linkages. Bioconjug Chem 13:822–830

    Article  PubMed  CAS  Google Scholar 

  • Zatsepin TS, Stetsenko DA, Gait MJ et al (2005) Use of carbonyl group addition—elimination reactions for synthesis of nucleic acid conjugates. Bioconjug Chem 16:471–489

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Pourceau G, Meyer A et al (2009) DNA-directed immobilisation of glycomimetics for glycoarrays application: comparison with covalent immobilisation, and development of an on-chip ic50 measurement assay. Biosens Bioelectron 24:2515–2521

    Article  PubMed  CAS  Google Scholar 

  • Zubin EM, Stetsenko DA, Zatsepin TS et al (2005) Oligonucleotides containing 2′-O-[2-(2,3-dihydroxypropyl)amino-2-oxoethyl]uridine as suitable precursors of 2′-aldehydo oligonucleotides for chemoselective ligation. Bioorg Med Chem 13:4912–4920

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We gratefully acknowledge our students, postdoctoral fellows, and colleagues who contributed to this work. Financial support to Prof. Eric Defrancq came from Cluster Région Rhone-Alpes, the Centre National pour la Recherche Scientifique (CNRS), and Université Joseph Fourier Grenoble 1. Dr. Yashveer Singh is supported by grant from NIH HIT-IT program (R01AI084137-01) to Prof. Patrick J. Sinko (PI).

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8022, USA

    Yashveer Singh

  2. Department of Chemistry, The University of Cambridge, Cambridge, CB2 1EW, UK

    Pierre Murat

  3. Département de Chimie Moléculaire, UMR CNRS 5250, Université Joseph Fourier, 53-38041, Grenoble cedex 9, France

    Nicolas Spinelli & Eric Defrancq

Authors
  1. Yashveer Singh
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  2. Pierre Murat
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  3. Nicolas Spinelli
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  4. Eric Defrancq
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Corresponding authors

Correspondence to Yashveer Singh or Eric Defrancq .

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Editors and Affiliations

  1. Institute of Chemistry/Biochemistry, Free University Berlin, Thielallee 63, Berlin, 14195, Berlin, Germany

    Volker A. Erdmann

  2. Inst. Bioorganic Chemistry, PAN Poznan, ul. Z. Noskowskiego 12/14, Poznan, 61-704, Poland

    Jan Barciszewski

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© 2012 Springer-Verlag Berlin Heidelberg

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Singh, Y., Murat, P., Spinelli, N., Defrancq, E. (2012). Oligonucleotide Conjugates: Rationale, Synthesis, and Applications. In: Erdmann, V., Barciszewski, J. (eds) From Nucleic Acids Sequences to Molecular Medicine. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27426-8_5

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