Chemical modifications: a field guide
A natural DNA or RNA strand would not survive minutes in the body. Chemical modification is what makes a therapeutic oligo stable, potent and selective. Here is how the main options compare.
Backbone modifications
The most widespread modification replaces one of the non bridging oxygens in the phosphate with sulfur, giving a phosphorothioate linkage. This single change dramatically slows nuclease degradation and improves binding to plasma proteins, which keeps the drug in circulation. Almost every approved single stranded oligo uses phosphorothioate linkages, at least at the ends.
Two prime sugar modifications
- Two prime O methyl (2'-OMe): a naturally occurring modification that boosts stability and binding affinity and lowers immune stimulation. Common in siRNA and ASO wings.
- Two prime methoxyethyl (2'-MOE): larger than O methyl, it gives strong nuclease resistance and high affinity, and features in several approved gapmer ASOs.
- Two prime fluoro (2'-F): a small substitution that raises affinity and is widely used in siRNA duplexes, often alternating with two prime O methyl.
Conformationally locked and non ionic chemistries
Locked nucleic acid, or LNA, adds a bridge that locks the sugar into an ideal shape for binding, giving very high affinity so that short, potent oligos become possible. Used carefully, because too much LNA can raise toxicity.
Morpholinos, or PMOs, replace the sugar phosphate backbone entirely with a neutral morpholine and phosphorodiamidate structure. They are uncharged, extremely stable and act purely by steric blocking, making them well suited to splice switching.
Choosing a modification strategy
There is no single best chemistry. Gapmers need an unmodified DNA core so RNase H can act, with modified wings for stability. siRNAs need patterns compatible with RISC. Splice switchers favour fully modified or non ionic chemistries that block without cutting.
The art is in the pattern, and the pattern is specific to each target and mechanism. Syngenis One treats the modification map as part of the design space, optimising it alongside the sequence rather than as an afterthought.
Related glossary terms
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