Efficient Synthesis of 2'-O-Methoxyethyl Oligonucleotide-Cationic Peptide Conjugates
Open access
Date
2021-11-19Type
- Journal Article
Abstract
Single-stranded phosphorothioate (PS) oligonucleotide drugs have shown potential for the treatment of several rare diseases. However, a barrier to their widespread use is that they exhibit activity in only a narrow range of tissues. One way to circumvent this constraint is to conjugate them to cationic cell-penetrating peptides (CPPs). Although there are several examples of morpholino and peptide nucleic acids conjugated with CPPs, there are noticeably few examples of PS oligonucleotide-CPP conjugates. This is surprising given that PS oligonucleotides presently represent the largest class of approved RNA-based drugs, including Nusinersen, that bears the 2'-O-methoxyethyl (MOE)-chemistry. In this work, we report a method for in-solution conjugation of cationic, hydrophobic peptides or human serum albumin to a 22-nucleotide MOE-PS oligonucleotide. Conjugates were obtained in high yields and purities. Our findings pave the way for their large-scale synthesis and testing in vivo. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000505642Publication status
publishedExternal links
Journal / series
ChemMedChemVolume
Pages / Article No.
Publisher
WileySubject
oligonucleotides; cell-penetrating peptides; bioconjugation; albumin conjugation; mass spectrometryOrganisational unit
03760 - Hall, Jonathan / Hall, Jonathan
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