DcpS as a therapeutic target for spinal muscular atrophy

Jasbir Singh, Michael Salcius, Shin Wu Liu, Bart L. Staker, Rama Mishra, John Thurmond, Gregory Michaud, Dawn R. Mattoon, John Printen, Jeffery Christensen, Jon Mar Bjornsson, Brian A. Pollok, Megerditch Kiledjian, Lance Stewart, Jill Jarecki*, Mark E. Gurney

*Corresponding author for this work

Research output: Contribution to journalArticle

92 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)711-722
Number of pages12
JournalACS chemical biology
Volume3
Issue number11
DOIs
StatePublished - Nov 21 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Fingerprint Dive into the research topics of 'DcpS as a therapeutic target for spinal muscular atrophy'. Together they form a unique fingerprint.

  • Cite this

    Singh, J., Salcius, M., Liu, S. W., Staker, B. L., Mishra, R., Thurmond, J., Michaud, G., Mattoon, D. R., Printen, J., Christensen, J., Bjornsson, J. M., Pollok, B. A., Kiledjian, M., Stewart, L., Jarecki, J., & Gurney, M. E. (2008). DcpS as a therapeutic target for spinal muscular atrophy. ACS chemical biology, 3(11), 711-722. https://doi.org/10.1021/cb800120t