Abnormally long r(CUG)n repeat expansion is believed to be the major cause of Myotonic dystrophy type 1 (DM1) because it binds to muscleblind-like 1 (MBNL 1) protein which regulates RNA splicing, leading to the mis-splicing of more than 100 pre-mRNAs. The rational design of oligomers with alternating bisamidine and melamine structure resulted in good binding affinity to the RNA target because of a multivalent effect. The oligomers also showed excellent activity in disrupting nuclear foci, reversing the mis-splicing of IR minigene, and sabotaging the toxic RNA biosynthesis. Excellent activity in Drosophila based DM1 models was also observed for the oligomers, rescuing the climbing ability of the flies upon oral treatment.