SiRNAs with Neutral Phosphate Triester Hydrocarbon Tails ExhibitCarrier-Free Gene-Silencing Activity

Short interfering RNAs (siRNAs) show promise as gene-silencing therapeutics, but their cellular uptake remains achallenge. We have recently shown the synthesis of siRNAs bearing a single neutral phenylethyl phosphotriester linkage within thesense strand. Here, we report the synthesis of siRNAs beari...

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Bibliographic Details
Published inACS medicinal chemistry letters Vol. 13; no. 4; pp. 695 - 700
Main Authors Hammill, Matthew L., Tsubaki, Kouta, Salim, Lidya, Varley, Andrew J., Giorgees, Ifrodet, Kitamura, Mitsuru, Okauchi, Tatsuo, Desaulniers, Jean-Paul
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 14.04.2022
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Carrier-free delivery
RNAi
RNAI THERAPEUTICS
INTERFERENCE
Short interfering RNA
Backbone modification
Phosphate triester
PRINCIPLES
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Summary:Short interfering RNAs (siRNAs) show promise as gene-silencing therapeutics, but their cellular uptake remains achallenge. We have recently shown the synthesis of siRNAs bearing a single neutral phenylethyl phosphotriester linkage within thesense strand. Here, we report the synthesis of siRNAs bearing three different hydrophobic phosphate triester linkages at keypositions within the sense strand and assess their gene silencing in the absence of a transfection carrier. The best siRNAs bearinghydrophobic phosphate triester tails were not aromatic and exhibited effective gene silencing (IC50 approximate to 56-141 nM), whereas thearomatic derivative with three hydrophobic tails did not exhibit carrier-free gene silencing
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.2c00027