5- C -Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease.
Atsushi KatoIzumi NakagomeUta KanekiyoTian-Tian LuYi-Xian LiKosuke YoshimuraMana KishidaKenta ShinzawaTomoki YoshidaNobutada TanakaYue-Mei JiaRobert J NashGeorge W J FleetChu-Yi YuPublished in: Journal of medicinal chemistry (2022)
In recent years, the function of pharmacological chaperones as a "thermodynamic stabilizer" has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5- C -heptyl-DNJ produced a nanomolar affinity for GAA with a K i value of 0.0047 μM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 μM 5- C -heptyl-DNJ increased the midpoint of the protein denaturation temperature ( T m ) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5- C -heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.
Keyphrases
- late onset
- heat shock
- combination therapy
- replacement therapy
- recombinant human
- heat shock protein
- ionic liquid
- molecular docking
- early onset
- protein protein
- case report
- working memory
- high throughput
- amino acid
- heat stress
- capillary electrophoresis
- smoking cessation
- binding protein
- mass spectrometry
- single molecule
- visible light