phosphorodiamidate

Phosphorodiamidate refers to a class of organophosphorus compounds in which a phosphorus atom bears a double bond to oxygen and is bonded to two amide-type substituents. In the context of nucleic acid chemistry, the term is most commonly encountered in phosphorodiamidate linkages used to construct phosphorodiamidate morpholino oligomers (PMOs). In these polymers, each phosphorus center carries a P=O bond, two P–N amide connections to morpholino rings, and a single P–O linkage to the adjacent unit, replacing the usual phosphate diester backbone of DNA or RNA.

Properties and significance: PMOs have a neutral, uncharged backbone, which contributes to high nucleic acid stability and reduced non-specific interactions. They exhibit strong resistance to nucleases and can support sequence-specific antisense activity, blocking translation or splicing of target RNAs.

Production and use: PMO backbones are assembled by phosphorodiamidate chemistry from morpholino nucleoside units using specialized phosphorodiamidite reagents; synthesis typically employs solid-phase methods. Therapeutically, PMOs function as antisense oligonucleotides and have been developed for gene silencing applications. Approved PMO drugs, such as eteplirsen and golodirsen for Duchenne muscular dystrophy in various regions, illustrate clinical utility.

Limitations and considerations: Delivery to target tissues remains a challenge; PMOs are generally well tolerated but require formulation for some uses; off-target effects and costs are considerations in therapy development.