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Author (up) Lee, M.M.; Childs-Disney, J.L.; Pushechnikov, A.; French, J.M.; Sobczak, K.; Thornton, C.A.; Disney, M.D. openurl 
  Title Controlling the Specificity of Modularly Assembled Small Molecules for RNA via Ligand Module Spacing: Targeting the RNAs That Cause Myotonic Muscular Dystrophy Type Journal Article
  Year 2009 Publication J. Am. Chem. Soc. Abbreviated Journal  
  Volume 131 Issue 47 Pages 17464-17472  
  Keywords Gene Role: BSU (Biological study, unclassified), BIOL (Biological study) (DMPK, RNA from; controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy); Proteins Role: BSU (Biological study, unclassified), BIOL (Biological study) (MBNL1 (Muscleblind-like 1 protein); controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy); Gene Role: BSU (Biological study, unclassified), BIOL (Biological study) (ZNF9, RNA from; controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy); Mutation (expansion, of repetitive DNA; controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy); Muscular dystrophy (myotonic; controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy); Molecular association (of MBNL1 with RNA repeats, disruption of; controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy); RNA Role: ADV (Adverse effect, including toxicity), BSU (Biological study, unclassified), BIOL (Biological study) (repetitive; controlling specificity of modularly assembled small mols. for RNA via ligand module spacing, targeting repetitive RNAs that interact with MBNL1 and cause myotonic muscular dystrophy)  
  Abstract Myotonic muscular dystrophy types 1 and 2 (DM1 and DM2, resp.) are caused by expansions of repeating nucleotides in noncoding regions of RNA. In DM1, the expansion is an rCUG triplet repeat, whereas the DM2 expansion is an rCCUG quadruplet repeat. Both RNAs fold into hairpin structures with periodically repeating internal loops sepd. by two 5'GC/3'CG base pairs. The sizes of the loops, however, are different: the DM1 repeat forms 1 * 1 nucleotide UU loops while the DM2 repeat forms 2 * 2 nucleotide 5'CU/3'UC loops. DM is caused when the expanded repeats bind the RNA splicing regulator Muscleblind-like 1 protein (MBNL1), thus compromising its function. Therefore, one potential therapeutic strategy for these diseases is to prevent MBNL1 from binding the toxic RNA repeats. Previously, we designed nanomolar inhibitors of the DM2-MBNL1 interaction by modularly assembling 6'-N-5-hexyonate kanamycin A (K) onto a peptoid backbone. The K ligand binds the 2 * 2 pyrimidine-rich internal loops found in the DM2 RNA with high affinity. The best compd. identified from that study contains three K modules sepd. by four propylamine spacing modules and is 20-fold selective for the DM2 RNA over the DM1 RNA. Because the modularly assembled K-contg. compds. also bound the DM1 RNA, albeit with lower affinity, and because the loop size is different, we hypothesized that the optimal DM1 RNA binder may display K modules sepd. by a shorter distance. Indeed, here the ideal DM1 RNA binder has only two propylamine spacing modules sepg. the K ligands. Peptoids displaying three and four K modules on a peptoid scaffold bind the DM1 RNA with Kd's of 20 nM (3-fold selective for DM1 over DM2) and 4 nM (6-fold selective) and inhibit the RNA-protein interaction with IC50's of 40 and 7 nM, resp. Importantly, by coupling the two studies together, we have detd. that appropriate spacing can affect binding selectivity by 60-fold (20- * 3-fold). The trimer and tetramer also bind .apprx.13- and .apprx.63-fold more tightly to DM1 RNAs than does MBNL1. The modularly assembled compds. are cell permeable and nontoxic as detd. by flow cytometry. The results establish that for these two systems: (i) a programmable modular assembly approach can provide synthetic ligands for RNA with affinities and specificities that exceed those of natural proteins; and, (ii) the spacing of ligand modules can be used to tune specificity for one RNA target over another.  
  Address Department of Chemistry and The Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0002-7863 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number refbase @ admin @ Serial 7312  
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