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Date: August 29, 2024
Time: 6am PDT / 9am EDT / 3pm CEST
Title: Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2’-O-Methyl Modified Single-Stranded Oligonucleotides
Description:
Single-stranded oligonucleotides (SSOs) are a rapidly expanding class of therapeutics. Chemical modifications such as the phosphorothioate (PS) backbone and the 2’-O-methyl (2’-OMe) ribose can improve the stability and pharmacokinetic properties of therapeutic SSOs, but they can also lead to toxicity in vitro and in vivo. In this study, we screened a mini library of 277 PS and 2’-OMe- modified SSOs, with or without mRNA complementarity, for cytotoxic properties in two cancer cell lines. Using circular dichroism, nucleic magnetic resonance, and molecular dynamics simulations, we show that PS- and 2’-OMe -modified SSOs that form stable hairpin structures through Watson–Crick base pairing are more likely to be cytotoxic than those that exist in an extended conformation. Overall, our study demonstrates a structure–cytotoxicity relationship and indicates that the formation of stable hairpins should be a consideration when designing SSOs toward optimal therapeutic profiles.
