造血器型プロスタグランジン D 合成酵素・阻害剤複合体の宇宙での 結晶化実験とデュシェンヌ型筋ジストロフィーの進行軽減薬の開発

抄録

Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes the cytoskeletal protein dystrophin. We have found that hematopoietic prostaglandin (PG) D synthase (H-PGDS) was induced in grouped necrotic muscle fibers in DMD patients. Oral administration of HPGDS inhibitor HQL-79 prevented the expansion of muscular necrosis in genetically dystrophin-deficient mdx mice and recovered the muscle strength. We obtained high quality crystals of H-PGDS-inhibitor complexes by crystallization under microgravity conditions within the International Space Station, determined X-ray crystallographic structures at a high resolution, and developed novel potent inhibitors highly selective to H-PGDS. The treatment of DMD dogs with a novel H-PGDS inhibitor prevented skeletal muscle atrophy and weakness without any side effects. These results indicate that H-PGDS inhibitors are useful for drug therapy of DMD patients.