Synthesis of mesyl phosphoramidate and phosphoryl guanidine oligonucleotides
Mesyl phosphoramidate (MsPA) and phosphoryl guanidine (PN) are new oligonucleotide backbone modifications that have shown promise in improving stability, binding affinity and specificity (and reducing toxicity) in antisense oligonucleotides (ASOs) and siRNA oligonucleotides, when compared with natural phosphodiester (PO) and phosphorothioate (PS) backbones.
The MsPA backbone has been reported to have a safer toxicity profile, while retaining specificity and binding affinity, relative to the canonical PS backbone. Like natural (PO) and PS backbones, the MsPA group is negatively charged in physiological conditions, and is a close mimic of the natural PO group. MsPA oligonucleotides (also called μ-oligonucleotides) have been shown to bind to mRNA and recruit RNase H (a prerequisite for the antisense effect). MsPA groups can either be interposed with other backbones (e.g. in gapmer ASOs), or at all internucleotide backbone positions.
We have refined our methods for the synthesis, purification and analysis of MsPA and PN oligonucleotides, and can now offer them at scale and at high purity, alongside other backbone and sugar modifications. We're excited to see how the MsPA and PN backbone modifications can be used to enhance our customers' antisense and siRNA projects.
Phosphoryl guanidine (PN) oligonucleotides (PGOs) are a new class of oligonucleotides with neutral backbones. Like PNA (peptide nucleic acid) oligonucleotides and PMOs (phosphorodiamidate morpholino oligonucleotides), PGOs have a neutral backbone. This makes them highly stable and resistant to nuclease degradation, and also allows them to more readily cross cell membranes (which allows them to be used at lower doses, making them less toxic). Unlike PNA oligonucleotides and PMOs, PGOs can be made using standard phosphoramidite chemistry, which makes them easier to synthesize at scale (and therefore more cost-effective), and also allows for the incorporation of PN backbones alongside other backbone modifications (e.g. in gapmers). The PN backbone has also been used in siRNA oligonucleotides.
