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Accessing Therapeutically-Relevant Multifunctional Antisense Oligonucleotide Conjugates Using Native Chemical

Daniel Engelhardt1,2, Peter Nordberg3, Laurent Knerr3

  • 1Research School of Chemistry, Australian National University, 2601, Canberra, ACT, Australia.

Angewandte Chemie (International Ed. in English)
|August 11, 2024
PubMed
Summary

Antisense oligonucleotide (ASO) therapies are advanced using native chemical ligation to create ASO-ligand conjugates. This method enables precise delivery and functionalization for treating genetic diseases.

Keywords:
bioconjugationdesulfurizationnative chemical ligationoligonucleotidesphosphorothioates

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Area of Science:

  • Molecular Medicine
  • Oligonucleotide Therapeutics
  • Chemical Biology

Background:

  • Antisense oligonucleotide (ASO) therapies offer precise gene expression modulation for various diseases.
  • Challenges in intracellular targeting and delivery of ASOs necessitate advanced conjugation strategies.
  • ASO-ligand conjugates are crucial for enhancing therapeutic efficacy and specificity.

Purpose of the Study:

  • To develop a versatile method for conjugating ASOs with therapeutic ligands using native chemical ligation.
  • To explore post-ligation functionalizations for creating multifunctional oligonucleotide constructs.
  • To demonstrate the applicability of this methodology for clinically relevant ASO conjugates.

Main Methods:

  • Utilized native chemical ligation to form stable amide linkages between ASOs and peptides/sugars.
  • Incorporated therapeutically relevant modifications like locked nucleic acids and phosphorothioate backbones.
  • Performed post-ligation functionalizations including radical desulfurization, lipidation, and alkylation.
  • Applied the method to create a triantennary-GalNAc ASO conjugate.

Main Results:

  • Successfully conjugated ASOs with various ligands and chemical modifications.
  • Demonstrated a range of post-ligation functionalizations yielding diverse molecular handles (alkyne, biotin, chelators).
  • Validated the binding and functional activity of a GalNAc-ASO conjugate, confirming applicability.

Conclusions:

  • Native chemical ligation provides a robust platform for creating functionalized ASO-ligand conjugates.
  • The developed methodology enhances ASO delivery and therapeutic potential.
  • This approach is applicable to the development of next-generation oligonucleotide-based therapeutics.