In:
ChemBioChem, Wiley, Vol. 17, No. 11 ( 2016-06-02), p. 985-989
Abstract:
Small interfering RNA (siRNA)‐mediated silencing requires siRNA loading into the RNA‐induced silencing complex (RISC). Presence of 5′‐phosphate (5′‐P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid‐domain of the Argonaute2 (Ago2) protein. Phosphorylation of exogenous duplex siRNAs is thought to be accomplished by cytosolic Clp1 kinase. However, although extensive chemical modifications are essential for siRNA–GalNAc conjugate activity, they can significantly impair Clp1 kinase activity. Here, we further elucidated the effect of 5′‐P on the activity of siRNA–GalNAc conjugates. Our results demonstrate that a subset of sequences benefit from the presence of exogenous 5′‐P. For those that do, incorporation of 5′‐( E )‐vinylphosphonate (5′‐VP), a metabolically stable phosphate mimic, results in up to 20‐fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability.
Type of Medium:
Online Resource
ISSN:
1439-4227
,
1439-7633
DOI:
10.1002/cbic.201600130
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
2019276-9
detail.hit.zdb_id:
2020469-3
SSG:
12
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