DcpS as a Therapeutic Target for Spinal Muscular Atrophy
Open Access
- 8 October 2008
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Chemical Biology
- Vol. 3 (11), 711-722
- https://doi.org/10.1021/cb800120t
Abstract
Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene, SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by 2-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-substituted quinazoline probe, we identified the scavenger decapping enzyme, DcpS, as a potential binder. We show that the C5-substituted quinazolines potently inhibit DcpS decapping activity and that the potency of inhibition correlates with potency for SMN2 promoter induction. Binding of C5-substituted quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m7GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule.Keywords
This publication has 29 references indexed in Scilit:
- Mechanistic and Kinetic Analysis of the DcpS Scavenger Decapping EnzymeOnline Journal of Public Health Informatics, 2008
- Insights into the Structure, Mechanism, and Regulation of Scavenger mRNA Decapping ActivityMolecular Cell, 2004
- Microarrays to characterize protein interactions on a whole‐proteome scaleProteomics, 2003
- Valproic acid increases SMN levels in spinal muscular atrophy patient cellsAnnals of Neurology, 2003
- DcpS can act in the 5′–3′ mRNA decay pathway in addition to the 3′–5′ pathwayProceedings of the National Academy of Sciences of the United States of America, 2003
- Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophyHuman Molecular Genetics, 2003
- The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatasesThe EMBO Journal, 2002
- Functional Link between the Mammalian Exosome and mRNA DecappingCell, 2001
- Effects of the heterogeneous nuclear ribonucleoprotein U (hnRNP U/SAF-A) on glucocorticoid-dependent transcription in vivoThe Journal of Steroid Biochemistry and Molecular Biology, 2001
- The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways.1999