Nature chemical biology, 2015-07, Vol.11 (7), p.511-517
- Palacino, James
- Swalley, Susanne E
- Song, Cheng
- Cheung, Atwood K
- Shu, Lei
- Zhang, Xiaolu
- Van Hoosear, Mailin
- Shin, Youngah
- Chin, Donovan N
- Keller, Caroline Gubser
- Beibel, Martin
- Renaud, Nicole A
- Smith, Thomas M
- Salcius, Michael
- Shi, Xiaoying
- Hild, Marc
- Servais, Rebecca
- Jain, Monish
- Deng, Lin
- Bullock, Caroline
- McLellan, Michael
- Schuierer, Sven
- Murphy, Leo
- Blommers, Marcel J J
- Blaustein, Cecile
- Berenshteyn, Frada
- Lacoste, Arnaud
- Thomas, Jason R
- Roma, Guglielmo
- Michaud, Gregory A
- Tseng, Brian S
- Porter, Jeffery A
- Myer, Vic E
- Tallarico, John A
- Hamann, Lawrence G
- Curtis, Daniel
- Fishman, Mark C
- Dietrich, William F
- Dales, Natalie A
- Sivasankaran, Rajeev
2015
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- Autor(en) / Beteiligte
- Palacino, James
- Swalley, Susanne E
- Song, Cheng
- Cheung, Atwood K
- Shu, Lei
- Zhang, Xiaolu
- Van Hoosear, Mailin
- Shin, Youngah
- Chin, Donovan N
- Keller, Caroline Gubser
- Beibel, Martin
- Renaud, Nicole A
- Smith, Thomas M
- Salcius, Michael
- Shi, Xiaoying
- Hild, Marc
- Servais, Rebecca
- Jain, Monish
- Deng, Lin
- Bullock, Caroline
- McLellan, Michael
- Schuierer, Sven
- Murphy, Leo
- Blommers, Marcel J J
- Blaustein, Cecile
- Berenshteyn, Frada
- Lacoste, Arnaud
- Thomas, Jason R
- Roma, Guglielmo
- Michaud, Gregory A
- Tseng, Brian S
- Porter, Jeffery A
- Myer, Vic E
- Tallarico, John A
- Hamann, Lawrence G
- Curtis, Daniel
- Fishman, Mark C
- Dietrich, William F
- Dales, Natalie A
- Sivasankaran, Rajeev
- Titel
- SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice
- Ist Teil von
- Nature chemical biology, 2015-07, Vol.11 (7), p.511-517
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1552-4450eISSN: 1552-4469DOI: 10.1038/nchembio.1837Titel-ID: cdi_pubmed_primary_26030728
- Format
- –
- Schlagworte
- Alternative Splicing, Animals, Binding Sites, Disease Models, Animal, Female, Gene Expression, Humans, Mice, Mice, Transgenic, Models, Molecular, Muscular Atrophy, Spinal - drug therapy, Muscular Atrophy, Spinal - metabolism, Muscular Atrophy, Spinal - mortality, Muscular Atrophy, Spinal - pathology, Protein Binding - drug effects, Protein Stability - drug effects, Proteolysis, Ribonucleoprotein, U1 Small Nuclear - agonists, Ribonucleoprotein, U1 Small Nuclear - chemistry, Ribonucleoprotein, U1 Small Nuclear - metabolism, RNA Precursors - agonists, RNA Precursors - chemistry, RNA Precursors - metabolism, RNA, Double-Stranded - agonists, RNA, Double-Stranded - chemistry, RNA, Double-Stranded - metabolism, Small Molecule Libraries - chemical synthesis, Small Molecule Libraries - metabolism, Small Molecule Libraries - pharmacology, Survival Analysis, Survival of Motor Neuron 2 Protein - chemistry, Survival of Motor Neuron 2 Protein - genetics, Survival of Motor Neuron 2 Protein - metabolism