Identification of metabolically stable 5'-phosphate analogs that support single-stranded siRNA activity

Nucleic Acids Research
Thazha P PrakashEric E Swayze

Abstract

The ss-siRNA activity in vivo requires a metabolically stable 5'-phosphate analog. In this report we used crystal structure of the 5'-phosphate binding pocket of Ago-2 bound with guide strand to design and synthesize ss-siRNAs containing various 5'-phosphate analogs. Our results indicate that the electronic and spatial orientation of the 5'-phosphate analog was critical for ss-siRNA activity. Chemically modified ss-siRNA targeting human apoC III mRNA demonstrated good potency for inhibiting ApoC III mRNA and protein in transgenic mice. Moreover, ApoC III ss-siRNAs were able to reduce the triglyceride and LDL cholesterol in transgenic mice demonstrating pharmacological effect of ss-siRNA. Our study provides guidance to develop surrogate phosphate analog for ss-siRNA and demonstrates that ss-siRNA provides an alternative strategy for therapeutic gene silencing.

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Citations

Apr 29, 2016·Chembiochem : a European Journal of Chemical Biology·Rubina ParmarVasant Jadhav
Apr 29, 2016·Nucleic Acid Therapeutics·Hannah M PendergraffJonathan K Watts
May 11, 2016·Bioorganic & Medicinal Chemistry Letters·Thazha P PrakashPunit P Seth
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Methods Mentioned

BETA
antisense oligonucleotides
transgenic
transfection
PCR
chemical modifications
dissection

Software Mentioned

ChemStation
GraphPad Prism
Prism

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