| Literature DB >> 26030728 |
James Palacino1, Susanne E Swalley1, Cheng Song1, Atwood K Cheung1, Lei Shu1, Xiaolu Zhang1, Mailin Van Hoosear1, Youngah Shin1, Donovan N Chin1, Caroline Gubser Keller2, Martin Beibel2, Nicole A Renaud1, Thomas M Smith1, Michael Salcius1, Xiaoying Shi1, Marc Hild1, Rebecca Servais1, Monish Jain1, Lin Deng1, Caroline Bullock1, Michael McLellan1, Sven Schuierer2, Leo Murphy1, Marcel J J Blommers2, Cecile Blaustein1, Frada Berenshteyn1, Arnaud Lacoste1, Jason R Thomas1, Guglielmo Roma2, Gregory A Michaud1, Brian S Tseng1, Jeffery A Porter1, Vic E Myer1, John A Tallarico1, Lawrence G Hamann1, Daniel Curtis1, Mark C Fishman1, William F Dietrich1, Natalie A Dales1, Rajeev Sivasankaran1.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2015 PMID： 26030728 DOI： 10.1038/nchembio.1837
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040