RNA Therapeutics Institute; Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology
Biochemistry | Molecular Biology
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 approximately 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.
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Citation: Nucleic Acids Res. 2015 Oct 15;43(18):8664-72. doi: 10.1093/nar/gkv942. Epub 2015 Sep 22. Link to article on publisher's site
DOI of Published Version
Nucleic acids research
Osborn, Maire F.; Alterman, Julia F.; Nikan, Mehran; Cao, Hong; Didiot, Marie C.; Hassler, Matthew R.; Coles, Andrew H.; and Khvorova, Anastasia, "Guanabenz (Wytensin) selectively enhances uptake and efficacy of hydrophobically modified siRNAs" (2015). Open Access Articles. 2586.
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