Phosphorothioates, essential components of therapeutic oligonucleotides

Area of Science:

• Biochemistry
• Molecular Biology
• Oligonucleotide Therapeutics

Background:

• Phosphorothioate linkages offer superior nuclease resistance compared to standard phosphate linkages in oligonucleotides.
• This chemical modification was initially adopted for antisense technology to enhance stability against enzymatic degradation.
• Accumulating evidence revealed additional benefits, including improved cellular uptake and in vivo bioavailability.

Observation:

• The majority of current therapeutic oligonucleotides incorporate phosphorothioate modifications.
• This review details the historical development and unique chemical properties of phosphorothioates.
• Applications extend beyond mRNA cleavage to include microRNAs, long noncoding RNAs, and decoy oligonucleotides.

Findings:

• Phosphorothioate modification is key to the efficacy of modern oligonucleotide therapeutics.
• The review covers diverse applications, including those not involving target RNA cleavage.
• Cellular uptake mechanisms are critical for therapeutic oligonucleotide function and are briefly reviewed.

Implications:

• Phosphorothioate chemistry is fundamental to the success of oligonucleotide-based drug development.
• Emerging roles in bacterial DNA suggest novel biological functions yet to be elucidated.
• Understanding these modifications is vital for advancing nucleic acid-based medicine and exploring new therapeutic strategies.