NMR structure of 2′-O-(2-methoxyethyl) modified and C5-methylated RNA dodecamer duplex

A major limitation for the development of more effective oligonucleotide therapeutics has been a lack of understanding of their penetration into the cytosol. While prior work has shown how backbone modifications affect cytosolic penetration, it is unclear how cytosolic penetration is affected by other features including base composition, base sequence, length, and degree of secondary structure. We have applied the chloroalkane penetration assay, which exclusively reports on material that reaches the cytosol, to investigate the effects of these characteristics on the cytosolic uptake of druglike oligonucleotides. We found that base composition and base sequence had moderate effects, while length did not correlate directly with the degree of cytosolic penetration. Investigating further, we found that the degree of secondary structure had the largest and most predictable correlations with cytosolic penetration. These methods and observations add a layer of design for maximizing the efficacy of new oligonucleotide therapeutics.

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Investigation of Sequence‐Penetration Relationships of Antisense Oligonucleotides

Batistatou

Kritzer

2023

ChemBioChem

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A two-residue nascent-strand steric gate controls synthesis of 2′-O-methyl- and 2′-O-(2-methoxyethyl)-RNA

et al. 2022

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Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2′-O-Methyl Modified Single-Stranded Oligonucleotides

Croft,

Fisher,

Barbhuiya

et al. 2024

Nucleic Acid Therapeutics

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NMR structure of 2′-O-(2-methoxyethyl) modified and C5-methylated RNA dodecamer duplex

Cited by 3 publications

References 24 publications

Investigation of Sequence‐Penetration Relationships of Antisense Oligonucleotides

Investigation of Sequence‐Penetration Relationships of Antisense Oligonucleotides

A two-residue nascent-strand steric gate controls synthesis of 2′-O-methyl- and 2′-O-(2-methoxyethyl)-RNA

Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2′-O-Methyl Modified Single-Stranded Oligonucleotides

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