69567-10-8Relevant articles and documents
5- C-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease
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
, p. 2329 - 2341 (2022/02/10)
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.
N-Alkylated Nitrogen-in-the-Ring Sugars: Conformational Basis of Inhibitiopn of Glycosidases and HIV-1 Replication
Asano, Naoki,Kizu, Haruhisa,Oseki, Kengo,Tomioka, Emiko,Matsui, Katsuhiko,et al.
, p. 2349 - 2356 (2007/10/02)
The conformations of nitrogen-in-the-ring sugars and their N-alkyl derivatives were studied from 1H NMR analyses, mainly using 3J(H,H) coupling constants and quantitative NOE experiments.No significant difference was seen in the ring conformation of 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), and N-butyl-1-deoxynojirimycin (3).Hiowever, it was shown that the C6 OH group in 1 is predominantly equatorial to the piperidine ring, while that in 2 or 3 is predominantly axial, and its N-alkyl group is oriented equatorially.In the furanose analogues 1,4-dideoxy-1,4-imino-D-arabinitol (4) and its N-methyl (5) and N-butyl (6) derivatives, the five-membered ring conformation differed significvantly by the presence or absence of the N-substituted group and the length of the N-alkyl chain.Compound 3 reduced its inhibitory effect on almost all glycosidases, resulting in an extremely specific inhibitor for processing α-glucosidase I since N-alkylation of 1 is known to enhance both the potency and specificity of this enzyme in vitro and in vivo.This preferred (C6 OH axial) conformation in 2 and 3 appears to be responsible for their strong α-glucosidase I activity.Compound 4 is a good inhibitor of intestinal α-glucohydrolases, α-glucosidase II, and Golgi α-mannosidases I and II, but is N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested.In the case of 2,5-dideoy-2,5-imino-D-mannitol (DMDP, 7), which is a potent toward β-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency β-galactosidase as well.N-alkylation of compounds 4 and 7, known well as potent yeast α-glucosidase inhibitors, resulted in a serious loss of inhi bitory activity toward yeast α-glucohydrolases.Activity of these nine sugar analogues against HIV-1 replication was determined, based on the inhibition of virus-induced cytopathogenicity in MT-4 and MOLT-4 cells.Compounds 2 and 3, which are better inhibitors of α-glucosidase I than 1, proved active with EC50 values of 69 and 49 μg/mL in MT-4 cells and 100 and 37 μg/mL in MOLT-4 cells, respectively, while none of the furanose analogues exhibited any inhibitory effects on HIV-1.The change in potency and specifity of bioactivity by N-alkylation of nitrogen-in-the-ring sugars appears to be correlated with their conformational change.
Moranoline derivatives and their production and the use of moranoline and its derivatives as a stabilizing agent for enzymes
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, (2008/06/13)
The present invention relates to stabilizing agents for enzymes which comprises an enzyme stabilizing amount of an N-substituted moranoline derivative of the formula (III): STR1 wherein R1 is phenyl lower alkynyl, phenoxy lower alkenyl or phenoxy lower alkynyl, wherein the phenyl moiety is unsubstituted, or a glucose oligomer thereof.
