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2'-Modified oligonucleotides for antisense therapeutics.

Thazha P Prakash1, Balkrishen Bhat

  • 1Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA. TPrakash@isisph.com

Current Topics in Medicinal Chemistry
|April 14, 2007
PubMed
Summary
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Second-generation antisense oligonucleotides with 2'-position chemical modifications show improved binding affinity, stability, and safety. These modifications enhance biophysical properties, making them promising for oligonucleotide therapeutics.

Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Molecular Biology

Background:

  • Chemically modified antisense oligonucleotides are advancing in clinical trials.
  • 2'-position modifications are the most successful chemical modifications to date.
  • Second-generation antisense oligonucleotides (ASOs) offer improved binding affinity, metabolic stability, and pharmacokinetic/toxicity profiles.

Purpose of the Study:

  • To review the structural and biophysical properties of 2"-modified nucleosides.
  • To highlight candidate nucleosides for oligonucleotide therapeutics.

Main Methods:

  • Review of structural and biophysical properties of selected 2"-modified nucleosides.
  • Analysis of how modifications influence sugar pucker, binding affinity, and nuclease resistance.

Related Experiment Videos

Main Results:

  • 2 -modifications enhance binding affinity and metabolic stability.
  • Modifications influencing 3 -endo sugar pucker improve affinity.
  • Gauche effect and charge effect modifications increase nuclease resistance.
  • Heterocyclic base modifications, like 2-thiothymine, additively enhance affinity with 2 -F and 2 -O-MOE.

Conclusions:

  • 2 -modified nucleosides possess favorable biophysical properties for oligonucleotide therapeutics.
  • These modifications are critical for enhancing the efficacy and safety of ASO drugs.