Modified internucleoside linkages for nuclease-resistant oligonucleotides.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Nucleic acid-based drugs show promise but face challenges with in vivo stability due to nuclease digestion.
• Modifying the internucleoside linkage is a key strategy to overcome these limitations and enhance drug properties.
• Recent advancements in antisense, siRNA, aptamer, and cyclic dinucleotide therapeutics highlight the need for stable nucleic acid structures.

Purpose of the Study:

• To review modified internucleoside linkages for nucleic acid therapeutics.
• To assess the impact of these modifications on annealing properties and nuclease resistance.
• To provide insights into the synthesis and incorporation of modified nucleotides for biological applications.

Main Methods:

• Literature review of modified internucleoside linkages.
• Analysis of studies evaluating annealing properties and nuclease resistance.
• Description of synthesis protocols for modified nucleotides and their incorporation into oligonucleotides.

Main Results:

• Various non-natural internucleoside linkages have been developed, significantly altering physico-chemical properties of nucleic acids.
• Modifications impact plasma stability, binding affinity, solubility, cell penetration, and biological activity.
• Focus is on linkages with demonstrated nuclease resistance for therapeutic potential.

Conclusions:

• Modified internucleoside linkages are essential for developing robust nucleic acid-based drugs.
• Understanding these modifications is critical for advancing nucleic acid therapeutics.
• This review consolidates knowledge on stable linkages for future drug development.