AMINOGLYCOSIDES AND USES THEREOF IN TREATING GENETIC DISORDERS

摘要

A new class of pseudo-trisaccharide aminoglycosides having an alkyl group at the 5″ position, exhibiting efficient stop codon mutation readthrough activity, low cytotoxicity and high selectivity towards eukaryotic translation systems are provided. Also provided are pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders, as well as processes of preparing these aminoglycosides. The disclosed aminoglycosides can be represented by the general formula I:;;or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of alkyl, cycloalkyl and aryl; and all other variables and features are as described in the specification.

主权项

1. A method for increasing the expression level of a gene having a premature stop-codon mutation, the method comprising translating the gene into a protein in the presence of a compound represented by general Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of alkyl, cycloalkyl and aryl; R2 is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB); R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; and a stereo-configuration of each of position 6′ and position 5″ is independently an R configuration or an S configuration, so as to readthrough said stop-codon, thereby increasing the expression level of the gene.