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Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides

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Abstract

A series of 3′-O-methylated-d-altrohexitol nucleoside analogs (MANA) was synthesized comprising all four base moieties, adenine, cytosine, uracil, and guanine. These monomers were incorporated into oligonucleotides (ONs) by automated solid phase synthesis and the thermal and thermodynamic stability of all new modified constructs were evaluated. Data were compared with results obtained for both anhydrohexitol (HNAs) and 3′-O-altrohexitol-modified ONs (ANAs). We hereby demonstrate that ONs modified with MANA monomers have an improved thermal and thermodynamic stability compared to RNA, ANA, or HNA containing ONs of which the extent depends on the number of incorporated moieties and their position in the sequence. Thermodynamic analysis afforded comparable or even improved results in comparison with the incorporation of locked nucleic acids. While the specificity of these new synthons is slightly lower compared to mismatches within RNA double strands, it is similar to the discrimination potential of other hexitol modifications (HNA and ANA) which already proved their biologic interest, highlighting the potential of MANA constructs in antisense and in siRNA applications.

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References

  1. Dean NM, Bennett CF (2003) Antisense oligonucleotide-based therapeutics for cancer. Oncogene 22: 9087–9096. doi:10.1038/sj.onc.1207231

    Article  CAS  Google Scholar 

  2. Hammond SM, Boettcher S, Caudy AA, Kobayashi R, Hannon GJ (2001) Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293: 1146–1150. doi:10.1126/science.1064023

    Article  CAS  Google Scholar 

  3. Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574. doi: http://dx.doi.org/10.1016/S0092-8674(02)00908-X

  4. Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (2005) 805 Human RISC couples microRNA biogenesis and posttran-scriptional gene silencing. Cell 123:631–640. doi:10.1016/j.cell.2005.10.022

  5. Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoharan M, Vornlocher H-P (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432: 173–178. doi:10.1038/nature03121

    Article  CAS  Google Scholar 

  6. De Paula D, Bentley MVLB, Mahato RI (2007) Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting. RNA 13: 431–456. doi:10.1261/rna.459807

    Article  CAS  Google Scholar 

  7. Chiu Y-L, Rana TM (2003) siRNA function in RNAi: a chemical modification analysis. RNA 9: 1034–1048. doi:10.1261/rna.5103703

    Article  CAS  Google Scholar 

  8. Mikat V, Heckel A (2007) Light-dependent RNA interference with nucleobase-caged siRNAs. RNA 13: 2341–2347. doi:10.1261/rna.753407

    Article  CAS  Google Scholar 

  9. Manoharan M (2004) RNA interference and chemically modified small interfering RNAs. Curr Opin Chem Biol 8: 570–579. doi:10.1016/j.cbpa.2004.10.007

    Article  CAS  Google Scholar 

  10. Van Aerschot A, Verheggen I, Hendrix C, Herdewijn P (1995) 1,5-Anhydrohexitol nucleic-acids, a new promising antisense construct. Angew Chem Int Ed 34: 1338–1339. doi:10.1002/anie.199513381

    Article  CAS  Google Scholar 

  11. Hendrix C, Rosemeyer H, Verheggen I, Seela F, Van Aerschot A, Herdewijn P (1997) 1′,5′-Anhydrohexitol oligonucleotides: synthesis, base pairing and recognition by regular oligodeoxyribonucleotides and oligoribonucleotides. Chem Eur J 3: 110–120. doi:10.1002/chem.19970030118

    Article  CAS  Google Scholar 

  12. Allart B, Khan K, Rosemeyer H, Schepers G, Hendrix C, Rothenbacher K, Seela F, Van Aerschot A, Herdewijn P (1999) d-Altritol nucleic acids (ANA): hybridisation properties, stability, and initial structural analysis. Chem Eur J 5:2424–2431. doi:http://dx.doi.org/10.1002/(SICI)1521-3765(19990802)5:8<2424::AID-CHEM2424>3.0.CO;2-W

  13. Wang J, Verbeure B, Luyten I, Lescrinier E, Froeyen M, Hendrix C, Rosemeyer H, Seela F, Van Aerschot A, Herdewijn P (2000) Cyclohexene nucleic acids (CeNA): serum stable oligonucleotides that activate RNase H and increase duplex stability with complementary RNA. J Am Chem Soc 122: 8595–8602. doi:10.1021/Ja000018+

    Article  CAS  Google Scholar 

  14. D’Alonzo D, Van Aerschot A, Guaragna A, Palumbo G, Schepers G, Capone S, Rozenski J, Herdewijn P (2009) Synthesis and base pairing properties of 1 ′,5 ′-anhydro-l-hexitol nucleic acids (l-HNA). Chem Eur J 15: 10121–10131. doi:10.1002/chem.200901847

    Article  Google Scholar 

  15. Martin P (1995) Ein neuer Zugang zu 2′- O-Alkylribonucleosiden und Eigenschaften deren Oligonucleotide. Helv Chim Acta 78: 486–504. doi:10.1002/hlca.19950780219

    Article  CAS  Google Scholar 

  16. Prakash TP, Bhat B (2007) 2′-Modified oligonucleotides for antisense therapeutics. Curr Top Med Chem 7: 641–649

    Article  CAS  Google Scholar 

  17. Tarköy M, Bolli M, Schweizer B, Leumann C (1993) Nucleic-acid analogues with constraint conformational flexibility in the sugar-phosphate backbone (‘bicyclo-DNA’) Part 1. Preparation of (3S,5′R)-2′-deoxy-3′,5′-ethano-α β-D-ribonucleosides (‘bicyclonucleosides’). Helv Chim Acta 76: 481–510. doi:10.1002/hlca.19930760132

    Article  Google Scholar 

  18. Singh SK, Nielsen P, Koshkin AA, Wengel J (1998) LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition. Chem Commun 455(456): 455–456. doi:10.1039/A708608C

    Article  Google Scholar 

  19. Veedu RN, Wengel J (2010) Locked nucleic acids: promising nucleic acid analogs for therapeutic applications. Chem Biodivers 7: 536–542. doi:10.1002/cbdv.200900343

    Article  CAS  Google Scholar 

  20. Herdewijn P (1996) Targeting RNA with conformationally restricted oligonucleotides. Liebigs Ann 1337(1348): 1337–1348. doi:10.1002/jlac.199619960902

    Google Scholar 

  21. Herdewijn P (2010) Nucleic acids with a six-membered ‘carbohydrate’ mimic in the backbone. Chem Biodivers 7: 1–59. doi:10.1002/cbdv.200900185

    Article  CAS  Google Scholar 

  22. Hendrix C, Rosemeyer H, De Bouvere B, Van Aerschot A, Seela F, Herdewijn P (1997) 1′,5′-anhydrohexitol oligonucleotides: hybridisation and strand displacement with oligoribonucleotides, interaction with RNase H and HIV reverse transcriptase. Chem Eur J 3: 1513–1520. doi:10.1002/chem.19970030920

    Article  CAS  Google Scholar 

  23. Vandermeeren M, Preveral S, Janssens S, Geysen J, Saison-Behmoaras E, Van Aerschot A, Herdewijn P (2000) Biological activity of hexitol nucleic acids targeted at Ha-ras and intracellular adhesion molecule-1 mRNA. Biochem Pharmacol 59: 655–663. doi:10.1016/S0006-2952(99)00367-6

    Article  CAS  Google Scholar 

  24. Fisher M, Abramov M, Van Aerschot A, Xu D, Juliano RL, Herdewijn P (2007) Inhibition of MDR1 expression with altritol-modified siRNAs. Nucl Acids Res 35: 1064–1074. doi:10.1093/nar/gkl1126

    Article  CAS  Google Scholar 

  25. Fisher M, Abramov M, Van Aerschot A, Rozenski J, Dixit V, Juliano RL, Herdewijn P (2009) Biological effects of hexitol and altritol-modified siRNAs targeting B-Raf. Eur J Pharmacol 606: 38–44. doi:10.1016/j.ejphar.2009.01.030

    Article  CAS  Google Scholar 

  26. Ovaere M, Sponer J, Sponer JE, Herdewijn P, Van Meervelt L (2012) How does hydroxyl introduction influence the double helical structure: the stabilization of an altritol nucleic acid:ribonucleic acid duplex. Nucl Acids Res 40: 7573–7583. doi:10.1093/nar/gks470

    Article  CAS  Google Scholar 

  27. Van Aerschot A, Meldgaard M, Schepers G, Volders F, Rozenski J, Busson R, Herdewijn P (2001) Improved hybridisation potential of oligonucleotides comprising O-methylated anhydrohexitol nucleoside congeners. Nucl Acids Res 29: 4187–4194. doi:10.1093/nar/29.20.4187

    Article  CAS  Google Scholar 

  28. Lamond AI, Sproat BS (1993) Antisense oligonucleotides made of 2′-O-alkylRNA: their properties and applications in RNA biochemistry. FEBS Lett 325: 123–127. doi:10.1016/0014-5793(93)81427-2

    Article  CAS  Google Scholar 

  29. Sproat BS, Lamond AI, Beijer B, Neuner P, Ryder U (1989) Highly efficient chemical synthesis of 2′-O-methyloligoribonucleotides and tetrabiotinylated derivatives; novel probes that are resistant to degradation by RNA or DNA specific nucleases. Nucl Acids Res 17: 3373–3386. doi:10.1093/nar/17.9.3373

    Article  CAS  Google Scholar 

  30. Abramov M, Herdewijn P (2007) Synthesis of altritol nucleoside phosphoramidites for oligonucleotide synthesis. Curr Protoc Nucl Acid Chem. Chapter 1:Unit 1.18. doi:10.1002/0471142700.nc0118s30

  31. Teste K, Colombeau L, Hadj-Bouazza A, Lucas R, Zerrouki R, Krausz P, Champavier Y (2008) Solvent-controlled regioselective protection of 5′-O-protected thymidine. Carbohydr Res 343: 1490–1495. doi:10.1016/j.carres.2008.04.026

    Article  CAS  Google Scholar 

  32. Lucas R, Teste K, Zerrouki R, Champavier Y, Guilloton M (2010) Chelation-controlled regioselective alkylation of pyrimidine 2′-deoxynucleosides. Carbohydr Res 345: 199–207. doi:10.1016/j.carres.2009.10.021

    Article  CAS  Google Scholar 

  33. Divakar KJ, Reese CB (1982) 4-(1,2,4-Triazol-1-yl) and 4- (3-nitro-1,2,4-triazol-1-yl)-1-(beta-D-2,3,5-tri- O-acetylarabinofur -anosyl)pyrimidin-2(1h)-ones-valuable intermediates in the synthesis of derivatives of ′′1-(beta- D-arabinofuranosyl)cytosine (Ara-C). J Chem Soc Perkin T 1: 1171–1176. doi:10.1039/P19820001171

    Article  Google Scholar 

  34. Ott G, Arnold L, Smrt J, Sobkowski M, Limmer S, Hofmann HP, Sprinzl M (1994) The chemical synthesis of biochemically active oligoribonucleotides using dimethylaminomethlene protected purine H-phosphonates. Nucleosides Nucleotides 13: 1069–1085. doi:10.1080/15257779408011880

    Article  CAS  Google Scholar 

  35. Van Aerschot A, Saison-Behmoaras E, Rozenski J, Hendrix C, Schepers G, Verhoeven G, Herdewijn P (1995) Bull Soc Chim Belg 104: 717

    Article  CAS  Google Scholar 

  36. Chatelain G, Brisset H, Chaix C (2009) A thermodynamic study of ferrocene modified hairpin oligonucleotides upon duplex formation: applications to the electrochemical detection of DNA. New J Chem 33: 1139–1147. doi:10.1039/B817057f

    Article  CAS  Google Scholar 

  37. Chatelain G, Meyer A, Morvan F, Vasseur JJ, Chaix C (2011) Electrochemical detection of nucleic acids using pentaferrocenyl phosphoramidate alpha-oligonucleotides. New J Chem 35: 893–901. doi:10.1039/C0nj00902d

    Article  CAS  Google Scholar 

  38. Bhattacharyya J, Maiti S, Muhuri S, Nakano S-i, Miyoshi D, Sugimoto N (2011) Effect of locked nucleic acid modifications on the thermal stability of noncanonical DNA structure. Biochemistry (Moscow) 50: 7414–7425. doi:10.1021/bi200477g

    Article  CAS  Google Scholar 

  39. Bramsen JB, Laursen MB, Nielsen AF, Hansen TB, Bus C, Langkjaer N, Babu BR, Hojland T, Abramov M, Van Aerschot A, Odadzic D, Smicius R, Haas J, Andree C, Barman J, Wenska M, Srivastava P, Zhou CZ, Honcharenko D, Hess S, Muller E, Bobkov GV, Mikhailov SN, Fava E, Meyer TF, Chattopadhyaya J, Zerial M, Engels JW, Herdewijn P, Wengel J, Kjems J (2009) A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity. Nucl Acids Res 37: 2867–2881. doi:10.1093/Nar/Gkp106

    Article  CAS  Google Scholar 

  40. Marky LA, Kallenbach NR, McDonough KA, Seeman NC, Breslauer KJ (1987) The melting behavior of a DNA junction structure: a calorimetric and spectroscopic study. Biopolymers 26: 1621–1634. doi:10.1002/bip.360260912

    Article  CAS  Google Scholar 

  41. Durand M, Chevrie K, Chassignol M, Thuong NT, Maurizot JC (1990) Circular dichroism studies of an oligodeoxyribonucleotide containing a hairpin loop made of a hexaethylene glycol chain: conformation and stability. Nucl Acids Res 18: 6353–6359. doi:10.1093/nar/18.21.6353

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium

    G. Chatelain, G. Schepers, J. Rozenski & Arthur Van Aerschot

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  1. G. Chatelain
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  2. G. Schepers
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  3. J. Rozenski
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  4. Arthur Van Aerschot
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Correspondence to Arthur Van Aerschot.

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Chatelain, G., Schepers, G., Rozenski, J. et al. Hybridization potential of oligonucleotides comprising 3′-O-methylated altritol nucleosides. Mol Divers 16, 825–837 (2012). https://doi.org/10.1007/s11030-012-9402-1

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