Abstract
We report synthesis and properties of a pair of new potent inhibitors of translation, namely two diastereomers of 7-methylguanosine 5'-(1-thiotriphosphate). These new analogs of mRNA 5'cap (referred to as m(7)GTPalphaS (D1) and (D2)) are recognized by translational factor eIF4E with high affinity and are not susceptible to hydrolysis by Decapping Scavenger pyrophosphatase (DcpS). The more potent of diastereomers, m(7)GTPalphaS (D1), inhibited cap-dependent translation in rabbit reticulocyte lysate approximately 8-fold and approximately 15-fold more efficiently than m(7)GTP and m(7)GpppG, respectively. Both analogs were also significantly more stable in RRL than unmodified ones.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Endoribonucleases / metabolism
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Eukaryotic Initiation Factor-4E / antagonists & inhibitors
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Eukaryotic Initiation Factor-4E / metabolism
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Guanosine Triphosphate / analogs & derivatives*
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Guanosine Triphosphate / chemical synthesis
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Guanosine Triphosphate / chemistry
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Guanosine Triphosphate / pharmacology
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Humans
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Mice
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Protein Biosynthesis
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Protein Synthesis Inhibitors / chemical synthesis
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Protein Synthesis Inhibitors / chemistry*
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Protein Synthesis Inhibitors / pharmacology*
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RNA Cap Analogs / chemical synthesis
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RNA Cap Analogs / chemistry*
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RNA Cap Analogs / pharmacology
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RNA Caps / antagonists & inhibitors*
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RNA Caps / metabolism
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RNA, Messenger / metabolism
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Stereoisomerism
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Thionucleotides / chemical synthesis
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Thionucleotides / chemistry
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Thionucleotides / pharmacology
Substances
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7-methylguanosine 5'-(1-thiotriphosphate)
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Eukaryotic Initiation Factor-4E
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Protein Synthesis Inhibitors
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RNA Cap Analogs
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RNA Caps
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RNA, Messenger
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Thionucleotides
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7-methylguanosine triphosphate
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Guanosine Triphosphate
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Endoribonucleases
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DcpS protein, human