Development of Readthrough Peptides from Dipeptiiic Antibiotics (+)-Negamycin for Duchenne Muscular Dystrophy Chemotherapy

摘要

Duchenne muscular dystrophy (DMD) is the most common children's muscular dystrophy, which primarily affects males and is characterized by progressive skeletal muscle weakness. A part of this genetic disease is caused by the defect in the muscle protein "dystrophin" by the nonsense mutation, which is a point mutation with a premature termination codon (PTC), namely stop codon, in the DNA sequence. Recently, it was reported that both the aminoglycoside antibiotic, gentamicin, and the less toxic (+)-negamycin 1 [1] restore dystrophin expression in skeletal and cardiac muscles of rndx mice, an animal model of DMD with the nonsense mutation in the dystrophin gene [2]. Hence, these compounds are recently designated as "readthrough compounds" that can skip PTC during protein biosynthesis and produce a functional protein with the full protein sequence. We focused on the dipeptidic antibiotics (+)-l (Figure 1) as a promising new therapeutic lead compound for the development of a DMD or other genetic disease drug caused by nonsense mutation.