Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching
Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3′-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5′CUG/3′GUC motif that binds the RNA splicin...
| Main Authors: | , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2014
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| Online Access: | http://hdl.handle.net/1721.1/84533 https://orcid.org/0000-0001-5016-0756 |
| _version_ | 1826205087045779456 |
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| author | Parkesh, Raman Childs-Disney, Jessica L. Nakamori, Masayuki Kumar, Amit Wang, Thomas Hoskins, Jason Thornton, Charles A. Disney, Matthew D. Housman, David E Wang, Eric T Tran, Tuan, M. Eng (Tuan Minh) Massachusetts Institute of Technology |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Parkesh, Raman Childs-Disney, Jessica L. Nakamori, Masayuki Kumar, Amit Wang, Thomas Hoskins, Jason Thornton, Charles A. Disney, Matthew D. Housman, David E Wang, Eric T Tran, Tuan, M. Eng (Tuan Minh) Massachusetts Institute of Technology |
| author_sort | Parkesh, Raman |
| collection | MIT |
| description | Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3′-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5′CUG/3′GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, sarco(endo)plasmic reticulum Ca[superscript 2+] ATPase 1, and cardiac troponin T. Based on these observations, the development of small-molecule ligands that target specifically expanded DM1 repeats could be of use as therapeutics. In the present study, chemical similarity searching was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of in vitro inhibitors of the RNA–protein complex were identified with low micromolar IC[subscript 50]’s, which are >20-fold more potent than the query compounds. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif–ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA–ligand interactions with chemical similarity searching. |
| first_indexed | 2024-09-23T13:06:32Z |
| format | Article |
| id | mit-1721.1/84533 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:06:32Z |
| publishDate | 2014 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/845332022-10-01T13:06:27Z Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching Parkesh, Raman Childs-Disney, Jessica L. Nakamori, Masayuki Kumar, Amit Wang, Thomas Hoskins, Jason Thornton, Charles A. Disney, Matthew D. Housman, David E Wang, Eric T Tran, Tuan, M. Eng (Tuan Minh) Massachusetts Institute of Technology Massachusetts Institute of Technology. Department of Biology Wang, Eric Wang, Thomas Housman, David E. Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3′-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5′CUG/3′GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, sarco(endo)plasmic reticulum Ca[superscript 2+] ATPase 1, and cardiac troponin T. Based on these observations, the development of small-molecule ligands that target specifically expanded DM1 repeats could be of use as therapeutics. In the present study, chemical similarity searching was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of in vitro inhibitors of the RNA–protein complex were identified with low micromolar IC[subscript 50]’s, which are >20-fold more potent than the query compounds. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif–ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA–ligand interactions with chemical similarity searching. 2014-01-27T13:44:29Z 2014-01-27T13:44:29Z 2012-02 2011-11 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/84533 Parkesh, Raman, Jessica L. Childs-Disney, Masayuki Nakamori, Amit Kumar, Eric Wang, Thomas Wang, Jason Hoskins, et al. “Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching.” Journal of the American Chemical Society 134, no. 10 (March 14, 2012): 4731-4742. https://orcid.org/0000-0001-5016-0756 en_US http://dx.doi.org/10.1021/ja210088v Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Parkesh, Raman Childs-Disney, Jessica L. Nakamori, Masayuki Kumar, Amit Wang, Thomas Hoskins, Jason Thornton, Charles A. Disney, Matthew D. Housman, David E Wang, Eric T Tran, Tuan, M. Eng (Tuan Minh) Massachusetts Institute of Technology Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching |
| title | Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching |
| title_full | Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching |
| title_fullStr | Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching |
| title_full_unstemmed | Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching |
| title_short | Design of a Bioactive Small Molecule That Targets the Myotonic Dystrophy Type 1 RNA via an RNA Motif–Ligand Database and Chemical Similarity Searching |
| title_sort | design of a bioactive small molecule that targets the myotonic dystrophy type 1 rna via an rna motif ligand database and chemical similarity searching |
| url | http://hdl.handle.net/1721.1/84533 https://orcid.org/0000-0001-5016-0756 |
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