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Proc Natl Acad Sci U S A. 2018 May 15;115(20):E4604-E4612. doi: 10.1073/pnas.1800260115. Epub 2018 Apr 30.

Mechanistic studies of a small-molecule modulator of SMN2 splicing.

Author information

1
California Institute for Biomedical Research, La Jolla, CA 92037.
2
California Institute for Biomedical Research, La Jolla, CA 92037; schultz@scripps.edu kjohnson@calibr.org.
3
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
4
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.

Abstract

RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the SMN2 gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA-binding ligands that modulate pre-mRNA splicing. Chemical proteomic and genomic techniques reveal that SMN-C2 directly binds to the AGGAAG motif on exon 7 of the SMN2 pre-mRNA, and promotes a conformational change in two to three unpaired nucleotides at the junction of intron 6 and exon 7 in both in vitro and in-cell models. This change creates a new functional binding surface that increases binding of the splicing modulators, far upstream element binding protein 1 (FUBP1) and its homolog, KH-type splicing regulatory protein (KHSRP), to the SMN-C2/C3-SMN2 pre-mRNA complex and enhances SMN2 splicing. These findings underscore the potential of small-molecule drugs to selectively bind RNA and modulate pre-mRNA splicing as an approach to the treatment of human disease.

KEYWORDS:

RG-7916; RNA binding; RNA splicing; chemical proteomics; spinal muscular atrophy

PMID:
29712837
PMCID:
PMC5960314
DOI:
10.1073/pnas.1800260115
[Indexed for MEDLINE]
Free PMC Article

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