5'-phosphorothiolate mRNA 5'-terminal (cap) analogs, mRNAs containing them, methods for obtaining them and methods for their use

摘要

The present invention relates to nucleotide, mRNA 5'-terminal (cap) analogs containing a sulfur atom at the 5 'position of 7-methylguanosine nucleoside. The disclosed compounds are recognized by the DcpS enzyme (decapping scavenger) (binding and non-hydrolyzing) and thus therapeutic uses as inhibitors thereof can be discovered. DcpS is a cap-specific enzyme with pyrophosphatase activity that has been identified as a therapeutic target in the treatment of spinal muscular atrophy (SMA). Some of the disclosed compounds have further modifications in the phosphate chain, which modulates the affinity for the DcpS enzyme. The present invention further relates to mRNA modified with a 5'-end (cap) analog at the 5 'end containing a 5'-phosphorothiolate moiety, wherein the mRNA has increased stability and translational activity in the cellular state. And the present invention relates to methods for their preparation, their use, and pharmaceutical formulations containing them. [Selection]