DcpS as a Therapeutic Target for Spinal Muscular Atrophy

Singh, J. J.; Salcius, Michael; Liu, Shin Wu; Staker, Bart L.; Mishra, Rama K.; Thurmond, John B.; Michaud, Gregory A.; Mattoon, Dawn; Printen, John A.; Christensen, Jeffery; Björnsson, Jón Már; Pollok, Brian A.; Kiledjian, Megerditch; Stewart, Lance; Jarecki, Jill; Gurney, Mark E.

doi:10.1021/cb800120t

Cited by 120 publications

(150 citation statements)

References 28 publications

(82 reference statements)

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“…RG3039 was initially identified and developed as a drug candidate for the treatment of SMA (Jarecki et al 2005;Singh et al 2008;Thurmond et al 2008) and can increase the survival of mouse models of SMA (Butchbach et al 2010;Gogliotti et al 2013;Van Meerbeke et al 2013). Despite it being a potent inhibitor of DcpS decapping (Singh et al 2008), the lack of detectable increase in SMN mRNA and protein in treated animals confounds the mechanism by which RG3039 promotes survival of SMA mice.…”

Section: Discussionmentioning

confidence: 99%

“…Despite it being a potent inhibitor of DcpS decapping (Singh et al 2008), the lack of detectable increase in SMN mRNA and protein in treated animals confounds the mechanism by which RG3039 promotes survival of SMA mice. Our results demonstrate that RG3039 can modulate RNA levels through its inhibition of DcpS as well as a mechanism independent of DcpS.…”

Section: Discussionmentioning

confidence: 99%

“…To determine whether the human DcpS decapping activity influences the expression of mRNAs in mammalian cells, we took advantage of a small molecule inhibitor of DcpS decapping, RG3039, to monitor changes in global mRNA levels. RG3039 is a cell-permeable quinazoline derivative that is a potent inhibitor of DcpS decapping (Singh et al 2008;Gogliotti et al 2013) and was used to inhibit cellular DcpS activity and monitor potential changes in RNA steady-state levels. RNA isolated from human SH-SY5Y retinoblastoma cells treated for 2 d with 100 nM RG3039 were analyzed on an Affymetrix U133 Plus 2.0 human microarray.…”

Section: Steady-state Levels Of Rnas Are Altered In Cells Treated Witmentioning

confidence: 99%

“…Cocrystal structures of a C5 substituted quinazoline compound, D156844, revealed it binds to the DcpS cap binding active site and inhibits its decapping (Singh et al 2008;Thurmond et al 2008). Further optimization generated the RG3039 derivative, which is also a potent DcpS decapping inhibitor (Gogliotti et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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DcpS is a transcript-specific modulator of RNA in mammalian cells

Zhou

Bail

Plasterer

et al. 2015

RNA

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The scavenger decapping enzyme DcpS is a multifunctional protein initially identified by its property to hydrolyze the resulting cap structure following 3 ′ end mRNA decay. In Saccharomyces cerevisiae, the DcpS homolog Dcs1 is an obligate cofactor for the 5 ′ -3 ′ exoribonuclease Xrn1 while the Caenorhabditis elegans homolog Dcs-1, facilitates Xrn1 mediated microRNA turnover. In both cases, this function is independent of the decapping activity. Whether DcpS and its decapping activity can affect mRNA steady state or stability in mammalian cells remains unknown. We sought to determine DcpS target genes in mammalian cells using a cell-permeable DcpS inhibitor compound, RG3039 initially developed for therapeutic treatment of spinal muscular atrophy. Global mRNA levels were examined following DcpS decapping inhibition with RG3039. The steady-state levels of 222 RNAs were altered upon RG3039 treatment. Of a subset selected for validation, two transcripts that appear to be long noncoding RNAs HS370762 and BC011766, were dependent on DcpS and its scavenger decapping catalytic activity and referred to as DcpS-responsive noncoding transcripts (DRNT) 1 and 2, respectively. Interestingly, only the increase in DRNT1 transcript was accompanied with an increase of its RNA stability and this increase was dependent on both DcpS and Xrn1. Importantly, unlike in yeast where the DcpS homolog is an obligate cofactor for Xrn1, stability of additional Xrn1 dependent RNAs were not altered by a reduction in DcpS levels. Collectively, our data demonstrate that DcpS in conjunction with Xrn1 has the potential to regulate RNA stability in a transcript-selective manner in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Steady-state Levels Of Rnas Are Altered In Cells Treated Witmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DcpS is a transcript-specific modulator of RNA in mammalian cells

Zhou

Bail

Plasterer

et al. 2015

RNA

Self Cite

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“…It has been proposed that either the cap structure or the decapping product serve as a signaling molecule for downstream functions. Recently, hDcpS has been identified as a molecular target of C5-quinazolines, which are potential therapeutics for spinal muscular atrophy (SMA) (Singh et al 2008). Inhibition of DcpS by these drugs increases the expression of the SMN2 gene, which can complement the defective levels of the survival motor neuron (SMN) protein causing SMA.…”

Section: Introductionmentioning

confidence: 99%

Affinity resins containing enzymatically resistant mRNA cap analogs—a new tool for the analysis of cap-binding proteins

Szczepaniak¹,

Zuberek²,

Darżynkiewicz³

et al. 2012

RNA

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Cap-binding proteins have been routinely isolated using m 7 GTP-Sepharose; however, this resin is inefficient for proteins such as DcpS (scavenger decapping enzyme), which interacts not only with the 7-methylguanosine, but also with the second cap base. In addition, DcpS purification may be hindered by the reduced resin capacity due to the ability of DcpS to hydrolyze m 7 GTP. Here, we report the synthesis of new affinity resins, m 7 GpCH 2 pp-and m 7 GpCH 2 ppA-Sepharoses, with attached cap analogs resistant to hydrolysis by DcpS. Biochemical tests showed that these matrices, as well as a hydrolyzable m 7 GpppA-Sepharose, bind recombinant mouse eIF4E specifically and at high capacity. In addition, purification of cap-binding proteins from yeast extracts confirmed the presence of all expected cap-binding proteins, including DcpS in the case of m 7 GpCH 2 pp-and m 7 GpCH 2 ppA-Sepharoses. In contrast, binding studies in vitro demonstrated that recombinant human DcpS efficiently bound only m 7 GpCH 2 ppA-Sepharose. Our data prove the applicability of these novel resins, especially m 7 GpCH 2 ppA-Sepharose, in biochemical studies such as the isolation and identification of cap-binding proteins from different organisms.

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Chirality and Biological Activity

Singh¹,

Hagen²

2010

Burger's Medicinal Chemistry and Drug Discovery

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The relationship between chirality and biological activity has been of increasing importance to the pharmaceutical and biopharmaceutical areas as evidenced by a growing number of chiral drugs that have been developed within the last two decades. This chapter covers several areas of importance in the design and synthesis of novel small molecule chiral drugs for medicinal chemists. The focus of this chapter is to provide an overview of the impact of chirality in medicinal chemistry and pharmaceutical sciences, and this should not be considered an exhaustive review of the topic. Several examples reported in the recent literature have been used to highlight the impact of chirality on development of therapeutics for various molecular targets. Chirality, as used in this chapter, also includes examples of atropisomers. The effects of chirality on pharmacological activities, absorption, distribution, metabolism, and excretion and toxicity are exemplified. In addition to chirality at carbon, examples of chiral compounds involving chirality at noncarbon atoms are included. A section on chirality in drug design provides several examples from recent literature covering diverse target classes. Regulatory considerations that apply to chiral drugs are addressed briefly. Section 10 covers recent drug development and marketed single enantiomers. Multiple synthetic approaches to produce chiral compounds with high enantiomeric purity, including chromatographic separation and enantioselective syntheses, were covered adequately in the 6th edition, and thus these areas and general definitions of chirality are not repeated in this chapter.

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DcpS as a Therapeutic Target for Spinal Muscular Atrophy

Cited by 120 publications

References 28 publications

DcpS is a transcript-specific modulator of RNA in mammalian cells

DcpS is a transcript-specific modulator of RNA in mammalian cells

Affinity resins containing enzymatically resistant mRNA cap analogs—a new tool for the analysis of cap-binding proteins

Chirality and Biological Activity

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