5'-Phosphorothiolate mRNA 5'-end (cap) Analogs, mRNA Comprising the Same, Method of Obtaining and Uses Thereof

摘要

The present invention relates to nucleotides, analogs of mRNA 5′-end (cap) containing sulfur atom at the position 5′ of 7-methylguanosine nucleoside. The disclosed compounds are recognized (bound and non-hydrolyzed) by DcpS enzyme (Decapping Scavenger), and thus may find therapeutic use as inhibitors thereof. DcpS is cap-specific enzyme with pyrophosphatase activity, which was identified as a therapeutic target in the treatment of spinal muscular atrophy (SMA). Some of the compounds disclosed have additional modifications in the phosphate chain, which modulate their affinity for DcpS enzyme. The present invention also relates to mRNAs modified at the 5′ end with mRNA 5′-end (cap) analogs containing 5′-phosphorothiolate moiety, which mRNAs have an increased stability and translational activity in cellular conditions, to a method of their preparation, their uses, and to a pharmaceutical formulation containing them, wherein L¹ and L² are independently selected from the group comprising O and S, wherein at least one of L¹ and L² is not O.;