title: High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides.
abstract: The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: B
authors: B
authors: Yang
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: X
authors: X
authors: Ming
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: C
authors: C
authors: Cao
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: B
authors: B
authors: Laing
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: A
authors: A
authors: Yuan
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: M A
authors: MA
authors: Porter
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: E A
authors: EA
authors: Hull-Ryde
authors: Southern Research Institute, Birmingham, AL 35205, USA.
authors: J
authors: J
authors: Maddry
authors: Southern Research Institute, Birmingham, AL 35205, USA.
authors: M
authors: M
authors: Suto
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA wjanzen@epizyme.com.
authors: W P
authors: WP
authors: Janzen
authors: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA arjay@med.unc.edu.
authors: R L
authors: RL
authors: Juliano
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004357:Drug Synergism; D057166:High-Throughput Screening Assays; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009841:Oligonucleotides / Q000032:analysis / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries