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Oligonucleotide⁻Palladacycle Conjugates as Splice-Correcting Agents.

Madhuri Hande1,2, Osama Saher3,4, Karin E Lundin5

  • 1Department of Chemistry, University of Turku, Vatselankatu 2, FIN-20014 Turku, Finland. nimamadhuri@gmail.com.

Molecules (Basel, Switzerland)
|March 29, 2019
PubMed
Summary

Modified oligonucleotides with metal groups show potential as splice-correcting therapeutic agents. These cyclopalladated compounds effectively altered splicing in cancer cells without causing toxicity, demonstrating feasibility for novel treatments.

Keywords:
oligonucleotideorganometallicpalladacyclepalladiumsplice-correction

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Area of Science:

  • Oligonucleotide chemistry
  • Medicinal chemistry
  • Molecular biology

Background:

  • Oligonucleotides are key in gene regulation and therapeutics.
  • Chemical modifications enhance oligonucleotide stability and function.
  • Cyclopalladated compounds offer unique chemical properties.

Purpose of the Study:

  • To synthesize and characterize 2'-O-Methylribo phosphorothioate oligonucleotides with cyclopalladated benzylamine conjugates.
  • To evaluate the hybridization properties and splice-switching activity of these modified oligonucleotides.
  • To assess the in vitro toxicity and therapeutic potential of the modified oligonucleotides.

Main Methods:

  • Synthesis of modified oligonucleotides with 5'-terminal cyclopalladated benzylamine groups.
  • UV melting experiments to determine duplex stability.
  • Splice-switching assays in human cancer cell lines (HeLa Luc/705, HuH7_705, U-2 OS_705).

Main Results:

  • Modified oligonucleotides exhibited melting temperatures approximately 5 °C lower than unmodified counterparts.
  • Cyclopalladated oligonucleotides demonstrated efficient splice-correction in HeLa Luc/705 cells.
  • No significant toxicity was observed in the tested cell lines.

Conclusions:

  • Covalently metalated oligonucleotides can be effectively used as splice-correcting agents.
  • The cyclopalladated modification enhances therapeutic potential without inducing cellular toxicity.
  • This study validates the feasibility of metalated oligonucleotides as novel therapeutic agents.