Identification of metabolically stable 5'-phosphate analogs that support single-stranded siRNA activity.
Nucleic Acids Res
; 43(6): 2993-3011, 2015 Mar 31.
Article
em En
| MEDLINE
| ID: mdl-25753666
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
RNA Interferente Pequeno
Tipo de estudo:
Diagnostic_studies
/
Guideline
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article