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Article Dans Une Revue Bioorganic and Medicinal Chemistry Année : 2018

Gymnotic delivery and gene silencing activity of reduction-responsive siRNAs bearing lipophilic disulfide-containing modifications at 2′-position

Résumé

Modified oligoribonucleotides used as siRNAs bearing biolabile disulfide-containing groups at some 2'-positions were synthesized following a post-synthesis transformation of solid-supported 2'-O-acetylthiomethyl RNA, previously described. Thus, the reduction-responsive and lipophilic benzyldithiomethyl (BnSSM) modification was introduced at different locations into siRNAs targeting the Ewing sarcoma EWS-Flil protein. Thermal stability, serum stability and response to glutathione treatment of modified siRNAs were thoroughly investigated. Among 17 modified siRNAs, significant gene silencing activities were demonstrated for the 8 most stable siRNAs in serum (half-life > 1 h) when using a transfection reagent. Of special interest, two naked 2'-O-BnSSM siRNAs transfection exhibited a remarkable gene silencing activity after 24 h incubation. These inhibitions are consistent with an efficient gymnotic delivery demonstrated by the presence of the corresponding fluorescent siRNAs within cells.
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Dates et versions

hal-02197153 , version 1 (27-08-2019)

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Florian Gauthier, Sandra Claveau, Jean-Rémi Bertrand, Jean-Jacques Vasseur, Christelle Dupouy, et al.. Gymnotic delivery and gene silencing activity of reduction-responsive siRNAs bearing lipophilic disulfide-containing modifications at 2′-position. Bioorganic and Medicinal Chemistry, 2018, 26 (16), pp.4635-4643. ⟨10.1016/j.bmc.2018.07.033⟩. ⟨hal-02197153⟩
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