Phosphorothioate analogs of m7GTP are enzymatically stable inhibitors of cap-dependent translation

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 m7GTPαS (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, m7GTPαS (D1), inhibited cap-dependent translation in rabbit reticulocyte lysate ∼8-fold and ∼15-fold more efficiently than m7GTP and m7GpppG, respectively. Both analogs were also significantly more stable in RRL than unmodified ones.

Graphical abstractThe synthesis and properties of new potent inhibitors of translation, two diastereomers of 7-methylguanosine 5′-(1-thiotriphosphate), are reported. These analogs of mRNA 5′cap are recognized by translational factor eIF4E with high affinity and are resistant to hydrolysis by Decapping Scavenger pyrophosphatase.Figure optionsDownload full-size imageDownload as PowerPoint slide