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Nucleic Acids Res. 2015 Oct 15;43(18):8664-72. doi: 10.1093/nar/gkv942. Epub 2015 Sep 22.

Guanabenz (Wytensin™) selectively enhances uptake and efficacy of hydrophobically modified siRNAs.

Author information

1
RNA Therapeutics Institute, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
RNA Therapeutics Institute, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA anastasia.khvorova@umassmed.edu.

Abstract

One of the major obstacles to the pharmaceutical success of oligonucleotide therapeutics (ONTs) is efficient delivery from the point of injection to the intracellular setting where functional gene silencing occurs. In particular, a significant fraction of internalized ONTs are nonproductively sequestered in endo-lysosomal compartments. Here, we describe a two-step, robust assay for high-throughput de novo detection of small bioactive molecules that enhance cellular uptake, endosomal escape, and efficacy of ONTs. Using this assay, we screened the LOPAC (Sigma-Aldrich) Library of Pharmacologically Active Compounds and discovered that Guanabenz acetate (Wytensin™), an FDA-approved drug formerly used as an antihypertensive agent, is capable of markedly increasing the cellular internalization and target mRNA silencing of hydrophobically modified siRNAs (hsiRNAs), yielding a ∼100-fold decrease in hsiRNA IC50 (from 132 nM to 2.4 nM). This is one of the first descriptions of a high-throughput small-molecule screen to identify novel chemistries that specifically enhance siRNA intracellular efficacy, and can be applied toward expansion of the chemical diversity of ONTs.

PMID:
26400165
PMCID:
PMC4605330
DOI:
10.1093/nar/gkv942
[Indexed for MEDLINE]
Free PMC Article

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