Seiichiro Ogawa

Publications (37) View all

• Article: Concise syntheses of potent chaperone drug candidates, N-octyl-4-epi-β-valinenamine (NOEV) and its 6-deoxy derivative, from (+)-proto-quercitol.

  Shinichi Kuno, Atsushi Takahashi, Seiichiro Ogawa
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  ABSTRACT: Described are the efficient syntheses of β-galactose-type unsaturated carbasugar amine, N-octyl-4-epi-β-valienamine (1a, NOEV) and 6-deoxy NOEV (12), starting from (+)-proto-quercitol (2), which is readily provided by the bioconversion of myo-inositol. NOEV is a potent chemical chaperone drug candidate for G(M1)-gangliosidosis. An intermediate alkadiene benzoate was prepared from 2 in five steps, with the key step being a Wittig reaction with an enol ester. The 6-deoxy derivative 12 was conveniently synthesized from the versatile intermediate dibromo compound 6, which was also an intermediate in the synthesis of NOEV. Enzyme inhibition assays demonstrated that 12 possessed stronger inhibitory activity than the parent 1a, suggesting that the C-6 position of the 4-epi-β-valienamine-type inhibitor could have hydrophobic interactions at the β-galactosidase active site residues.
  Carbohydrate research 12/2012; 368C:8. · 2.03 Impact Factor
• Article: Molecular Basis of Chemical Chaperone Effects of N-octyl-β-valienamine on Human β-glucosidase in Low/neutral pH Conditions

  Jo Hiroyuki, Yugi Katsuyuki, Ogawa Seiichiro, Suzuki Yoshiyuki, Sakakibara Yasubumi
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  ABSTRACT: Chemical chaperone therapy is a strategy for restoring the activities of mutant lysosomal hydrolases. Thistherapy involves chemical compounds binding to the dysfunctional enzymes. The chemical chaperones for lysosomalhydrolases are anticipated to stabilize folding of target enzymes by binding at neutral pH and rescuing enzymeactivities by dissociation in acidic conditions after transport to lysosome. However, the molecular basis describing themechanism of action of chemical chaperones has not been analysed sufficiently. Here we present results derived frommolecular dynamics simulations showing that the binding free energy between human b-glucosidase and its knownchemical chaperone, N-octyl-b-valienamine (NOV), is lower at pH 7 than at pH 5. This observation is consistent withthe hypothetical activity of chemical chaperones. The pH conditions were represented as differences in the protonationstates of ionizable residues which were determined from predicted pKa values. The binding free energy change isnegatively correlated to the number of hydrogen bonds (H-bonds) formed between GLU235, the acid/base catalyst ofthe enzyme, and the N atom of NOV. At pH 7, NOV is inserted further into the active site than at pH 5. Consequently,this provides an increase in the number of H-bonds formed. Thus, we conclude that the dissociation of NOV fromb-glucosidase at pH 5 occurs due to an increase in the binding free energy change caused by protonation of severalresidues which decreases the number of H-bonds formed between NOV and the enzyme.
  Journal of Proteomics & Bioinformatics. 01/2010;
• Article: Therapeutic chaperone effect of N-octyl 4-epi-β-valienamine on murine G(M1)-gangliosidosis.

  Yoshiyuki Suzuki, Satoshi Ichinomiya, Mieko Kurosawa, Junichiro Matsuda, Seiichiro Ogawa, Masami Iida, Takatoshi Kubo, Miho Tabe, Masayuki Itoh, Katsumi Higaki, Eiji Nanba, Kousaku Ohno
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  ABSTRACT: Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-β-valienamine (NOEV) was studied in G(M1)-gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal excretion after oral administration. Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood-brain barrier to induce high expression of the apparently deficient β-galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months. Survival time was significantly prolonged. This result suggests that NOEV chaperone therapy will be clinically effective for prevention of neuronal damage if started early in life hopefully also in human patients with G(M1)-gangliosidosis.
  Molecular Genetics and Metabolism 03/2012; 106(1):92-8. · 3.19 Impact Factor
• Article: Transformation of quercitols into 4-methylenecyclohex-5-ene-1,2,3-triol derivatives, precursors for the chemical chaperones N-octyl-4-epi-β-valienamine (NOEV) and N-octyl-β-valienamine (NOV).

  Shinichi Kuno, Atsushi Takahashi, Seiichiro Ogawa
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  ABSTRACT: (+)-proto-Quercitol (1) and (-)-vibo-quercitol (2), both of which could be readily prepared by the bioconversion of myo-inositol, were successfully converted into the corresponding 4-methylenecyclohex-5-ene-1,2,3-triol derivatives. These compounds were demonstrated to be suitable precursors, preserving their configurations, for bioactive carba-aminosugars such as the potent chemical chaperone drug candidates, N-octyl-4-epi-β-valienamine (NOEV, 3) and N-octyl-β-valienamine (NOV, 4).
  Bioorganic & medicinal chemistry letters 12/2011; 21(23):7189-92. · 2.65 Impact Factor
• Article: Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency.

  Katsumi Higaki, Linjing Li, Udin Bahrudin, Soichiro Okuzawa, Ayumi Takamuram, Koichi Yamamoto, Kaori Adachi, Rubigilda C Paraguison, Tomoko Takai, Hiroki Ikehata, Lika Tominaga, Ichiro Hisatome, Masami Iida, Seiichiro Ogawa, Junichiro Matsuda, Haruaki Ninomiya, Yasubumi Sakakibara, Kousaku Ohno, Yoshiyuki Suzuki, Eiji Nanba
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  ABSTRACT: β-Galactosidase deficiency is a group of lysosomal lipid storage disorders with an autosomal recessive trait. It causes two clinically different diseases, G(M1) -gangliosidosis and Morquio B disease. It is caused by heterogeneous mutations in the GLB1 gene coding for the lysosomal acid β-galactosidase. We have previously reported the chaperone effect of N-octyl-4-epi-β-valienamine (NOEV) on mutant β-galactosidase proteins. In this study, we performed genotype analyses of patients with β-galactosidase deficiency and identified 46 mutation alleles including 9 novel mutations. We then examined the NOEV effect on mutant β-galactosidase proteins by using six strains of patient-derived skin fibroblast. We also performed mutagenesis to identify β-galactosidase mutants that were responsive to NOEV and found that 22 out of 94 mutants were responsive. Computational structural analysis revealed the mode of interaction between human β-galactosidase and NOEV. Moreover, we confirmed that NOEV reduced G(M1) accumulation and ameliorated the impairments of lipid trafficking and protein degradation in β-galactosidase deficient cells. These results provided further evidence to NOEV as a promising chaperone compound for β-galactosidase deficiency.
  Human Mutation 04/2011; 32(7):843-52. · 5.69 Impact Factor