title: The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides.
abstract: The attainment of strong pharmacological effects with oligonucleotides is hampered by inefficient access of these molecules to their sites of action in the cytosol or nucleus. Attempts to address this problem with lipid or polymeric delivery systems have been only partially successful. Here, we describe a novel alternative approach involving the use of a non-toxic small molecule to enhance the pharmacological effects of oligonucleotides. The compound Retro-1 was discovered in a screen for small molecules that reduce the actions of bacterial toxins and has been shown to block the retrograde trafficking pathway. We demonstrate that Retro-1 can also substantially enhance the effectiveness of antisense and splice switching oligonucleotides in cell culture. This effect occurs at the level of intracellular trafficking or processing and is correlated with increased oligonucleotide accumulation in the nucleus but does not involve the perturbation of lysosomal compartments. We also show that Retro-1 can alter the effectiveness of splice switching oligonucleotides in the in vivo setting. These observations indicate that it is possible to enhance the pharmacological actions of oligonucleotides using non-toxic and non-lysosomotropic small molecule adjuncts.
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Xin
authors: X
authors: Ming
authors: Kyle
authors: K
authors: Carver
authors: Michael
authors: M
authors: Fisher
authors: Romain
authors: R
authors: Noel
authors: Jean-Christophe
authors: JC
authors: Cintrat
authors: Daniel
authors: D
authors: Gillet
authors: Julien
authors: J
authors: Barbier
authors: Canhong
authors: C
authors: Cao
authors: John
authors: J
authors: Bauman
authors: Rudolph L
authors: RL
authors: Juliano
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009841:Oligonucleotides / Q000032:analysis / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012326:RNA Splicing / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C549072:7-bromo-5-phenyl-4-propionyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one; D001570:Benzodiazepinones; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering
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