title: Reducing levels of toxic RNA with small molecules.
abstract: Myotonic dystrophy (DM) is one of the most common forms of muscular dystrophy. DM is an autosomal dominant disease caused by a toxic gain of function RNA. The toxic RNA is produced from expanded noncoding CTG/CCTG repeats, and these CUG/CCUG repeats sequester the Muscleblind-like (MBNL) family of RNA binding proteins. The MBNL proteins are regulators of alternative splicing, and their sequestration has been linked with mis-splicing events in DM. A previously reported screen for small molecules found that pentamidine was able to improve splicing defects associated with DM. Biochemical experiments and cell and mouse model studies of the disease indicate that pentamidine and related compounds may work through binding the CTG*CAG repeat DNA to inhibit transcription. Analysis of a series of methylene linker analogues of pentamidine revealed that heptamidine reverses splicing defects and rescues myotonia in a DM1 mouse model.
authors.affiliation: Institute of Molecular Biology and §Department of Chemistry and Biochemistry, University of Oregon , Eugene, Oregon 97403, United States.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Coonrod
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.forename: Wenli
authors.initials: W
authors.lastname: Wang
authors.forename: Samuel
authors.initials: S
authors.lastname: Carrell
authors.forename: Cameron L
authors.initials: CL
authors.lastname: Hilton
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Bodner
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Siboni
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Docter
authors.forename: Michael M
authors.initials: MM
authors.lastname: Haley
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Berglund
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D009223:Myotonic Dystrophy; D010419:Pentamidine / Q000737:chemistry / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D012313:RNA; D010419:Pentamidine
references.citation: Nucleic Acids Res. 2008 Mar;36(5):1654-64
references.pmid: 18263620
references.citation: Biochemistry. 1992 Aug 11;31(31):7104-9
references.pmid: 1643044
references.citation: J Med Chem. 1990 Apr;33(4):1252-7
references.pmid: 2319567
references.citation: Nucleic Acids Res. 2012 Jul;40(13):6380-90
references.pmid: 22492623
references.citation: J Am Chem Soc. 2009 Jul 22;131(28):9767-79
references.pmid: 19552411
references.citation: Mol Cell. 2002 Jul;10(1):35-44
references.pmid: 12150905
references.citation: J Biol Chem. 2005 Apr 29;280(17):16949-54
references.pmid: 15722335
references.citation: Mol Ecol. 2002 Dec;11(12):2453-65
references.pmid: 12453231
references.citation: Org Lett. 2010 Jan 15;12(2):216-9
references.pmid: 20000489
references.citation: Differentiation. 2006 Mar;74(2-3):65-80
references.pmid: 16533306
references.citation: Mol Ther. 2003 May;7(5 Pt 1):670-80
references.pmid: 12718910
references.citation: RNA. 2007 Dec;13(12):2238-51
references.pmid: 17942744
references.citation: Nucleic Acids Res. 2011 Nov 1;39(20):8881-90
references.pmid: 21768123
references.citation: Nat Struct Mol Biol. 2010 Feb;17(2):187-93
references.pmid: 20098426
references.citation: J Biol Chem. 1998 Oct 9;273(41):26998-7008
references.pmid: 9756950
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16068-73
references.pmid: 19805260
references.citation: FEBS Lett. 2006 Oct 2;580(22):5399-405
references.pmid: 16989817
references.citation: Nat Genet. 1998 Apr;18(4):378-81
references.pmid: 9537423
references.citation: Hum Mol Genet. 2007 Dec 1;16(23):2834-43
references.pmid: 17728322
references.citation: J Am Chem Soc. 2012 Mar 14;134(10):4731-42
references.pmid: 22300544
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9203-8
references.pmid: 19470458
references.citation: Nature. 1992 Feb 6;355(6360):545-6
references.pmid: 1346923
references.citation: Gene Ther. 2009 Feb;16(2):211-7
references.pmid: 18923454
references.citation: Neurosci Lett. 2009 Dec 4;466(2):99-102
references.pmid: 19647781
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18551-6
references.pmid: 19822739
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Hum Mol Genet. 2005 Aug 1;14(15):2189-200
references.pmid: 15972723
references.citation: Nat Cell Biol. 2005 Dec;7(12):1240-7
references.pmid: 16273094
references.citation: Annu Rev Neurosci. 2006;29:259-77
references.pmid: 16776586
references.citation: Science. 2009 Jul 17;325(5938):336-9
references.pmid: 19608921
references.citation: Biochim Biophys Acta. 1997 Feb 7;1350(2):189-204
references.pmid: 9048889
references.citation: Cell. 2009 Feb 20;136(4):777-93
references.pmid: 19239895
references.citation: ACS Chem Biol. 2009 May 15;4(5):345-55
references.pmid: 19348464
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11866-71
references.pmid: 21730182
references.citation: Nucleic Acids Res. 2011 Sep 1;39(17):7444-54
references.pmid: 21666257
references.citation: RNA. 2000 Jul;6(7):937-51
references.pmid: 10917591
references.citation: Science. 2003 Dec 12;302(5652):1978-80
references.pmid: 14671308
references.citation: Gene Ther. 2003 May;10(9):795-802
references.pmid: 12704419
references.citation: EMBO J. 2000 Sep 1;19(17):4439-48
references.pmid: 10970838
references.citation: Biochemistry. 1993 Apr 20;32(15):4098-104
references.pmid: 7682441
references.citation: J Am Chem Soc. 2008 Dec 3;130(48):16254-61
references.pmid: 18998634
references.citation: J Biol Chem. 2009 Mar 20;284(12):7419-23
references.pmid: 18957432
references.citation: J Biol Chem. 2010 Aug 13;285(33):25426-37
references.pmid: 20519504
references.citation: Science. 2000 Sep 8;289(5485):1769-73
references.pmid: 10976074
references.citation: Cell. 2012 Feb 17;148(4):690-701
references.pmid: 22341442
references.citation: Science. 2001 Aug 3;293(5531):864-7
references.pmid: 11486088
references.citation: EMBO J. 2004 Aug 4;23(15):3103-12
references.pmid: 15257297
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4221-6
references.pmid: 22371589
references.citation: Biochem J. 1997 Apr 1;323 ( Pt 1):23-31
references.pmid: 9173886
references.citation: Nature. 2012 Aug 2;488(7409):111-5
references.pmid: 22859208
references.citation: Cell. 2012 Aug 17;150(4):710-24
references.pmid: 22901804
references.citation: J Biol Chem. 2011 Sep 30;286(39):34224-33
references.pmid: 21832083
references.citation: Science. 1992 Mar 6;255(5049):1253-5
references.pmid: 1546325
references.citation: ACS Chem Biol. 2012 May 18;7(5):856-62
references.pmid: 22332923
references.citation: Biochim Biophys Acta. 2007 Feb;1772(2):195-204
references.pmid: 16876389
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13915-20
references.pmid: 19667189
references.citation: PLoS One. 2012;7(11):e48825
references.pmid: 23166594