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Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.

Abstract：

:Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Prakash TP,Kinberger GA,Murray HM,Chappell A,Riney S,Graham MJ,Lima WF,Swayze EE,Seth PP

doi

10.1016/j.bmcl.2016.04.063

subject

Has Abstract

pub_date

2016-06-15 00:00:00

pages

2817-2820

issue

12

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)30439-5

journal_volume

26

pub_type

杂志文章

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