Fosforotioaattilinkkejä

Fosforotioaattilinkkejä, also known as phosphorothioate linkages, are a modified internucleotide bond in nucleic acids. In a natural phosphodiester bond, a phosphate group links two sugar molecules. In a phosphorothioate linkage, one of the non-bridging oxygen atoms in the phosphate group is replaced by a sulfur atom. This substitution significantly alters the chemical properties of the linkage.

The introduction of sulfur into the phosphate backbone makes the linkage more resistant to nuclease degradation. Nucleases are enzymes that break down nucleic acids, and their activity is a key factor in the stability and lifespan of DNA and RNA in biological systems and in vitro. The increased stability of phosphorothioate linkages is a primary reason for their use in therapeutic applications.

Oligonucleotides containing phosphorothioate linkages are commonly employed as antisense agents and small interfering RNAs (siRNAs). These therapeutic molecules are designed to target specific mRNA molecules, thereby modulating gene expression. Their enhanced resistance to nucleases allows them to persist longer in the body, increasing their efficacy.

The synthesis of phosphorothioate linkages can be achieved through various chemical methods, typically involving the oxidation of a phosphite triester intermediate with elemental sulfur. While conferring increased stability, the sulfur atom can introduce chirality at the phosphorus atom, leading to a mixture of diastereomers in the final oligonucleotide. This can sometimes affect binding affinity and nuclease resistance. Despite these considerations, phosphorothioate chemistry remains a cornerstone in the development of oligonucleotide-based therapeutics.