Amino abasic building blocks tune siRNA potency, off-target effects and liver exposure
- Four phosphoramidite building blocks lacking a nucleobase, built on pyrrolidine and aminocyclopentane cores, were prepared for placing into siRNA strands.
- Sense-strand placement loosened the duplex depending on position; central or terminal sites boosted silencing, with the (S)-cyclopentane isomer best.
- Putting the (R)-cyclopentane isomer in the seed region curbed miRNA-like off-targeting without losing on-target effect, including in mice.
- The (S) unit at the 3' end also improved nuclease stability and liver exposure, and doubled as a handle for conjugation.
💡 Points Based on the abstract
Unlike GNA or UNA, which destabilize the duplex mainly through added flexibility in the seed, these amino abasic units also carry a conjugation handle, and stereochemistry seems to separate potency from off-target behavior. That (R)/(S) split is intriguing, but I'd want melting data, Ago2 loading, and a head-to-head against GNA at the same seed position before calling it an upgrade.