- 5- C-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease
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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 Ki 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 (Tm) 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.
- Kato, Atsushi,Nakagome, Izumi,Kanekiyo, Uta,Lu, Tian-Tian,Li, Yi-Xian,Yoshimura, Kosuke,Kishida, Mana,Shinzawa, Kenta,Yoshida, Tomoki,Tanaka, Nobutada,Jia, Yue-Mei,Nash, Robert J.,Fleet, George W. J.,Yu, Chu-Yi
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p. 2329 - 2341
(2022/02/10)
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- Method for the treatment of Pompe disease using 1-deoxynojirimycin and derivatives
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The present invention provides a method for increasing the activity of a mutant or wild-type α-glucosidase enzyme in vitro and in vivo by contacting the enzyme with a specific pharmacological chaperone which is a derivative of 1-deoxynojirimycin. The inve
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- COMPOSITIONS COMPRISING NB-DNJ, NE-DNJ OR D-GLUCARO-DELTA-LACTAM AND THEIR USES FOR THE TREATMENT OF PAIN AND OTHER NEUROLOGICAL CONDITIONS
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Methods and compositions for the treatment of conditions including stress-associated, chronic pain, and neurodegenerative conditions in a mammal using a composition comprising NB-DNJ or a compound structurally similar thereto.
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Page/Page column 47
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