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Journal Name
Medicinal Chemistry Communications
DOI: 10.1039/C4MD00270A
trafficking the mutant protein into the lysosome, to reduce the
substrate burden and to prevent neurological deterioration in the
next study. Moreover, the present structural modification
strategy could also help the development of novel and potent
chaperones for other lysosomal storage diseases.
6
(a) K. Fantur, D. Hofer, G. Schitter, A. J. Steiner, B. M. Pabst, T. M.
Wrodnigg, A. E. Stütz and E. Paschke, Mol. Genet. Metab., 2010,
100, 262; (b) R. F. G. Fröhlich, R. H. Furneaux, D. J. Mahuran, R.
Saf, A. E. Stütz, M. B. Tropak, J. Wicki, S. G. Withers and T. M.
Wrodnigg, Carbohydr. Res., 2011, 346, 1592; (c) B. A. Rigat, M. B.
Tropak, J. Buttner, E. Crushell, D. Benedict, J. W. Callahan, D. R.
Martin and D. J. Mahuran, Mol. Genet. Metab., 2012, 107, 203; (d)
M. AguilarꢀMoncayo, T. Takai, K. Higaki, T. MenaꢀBarragán, Y.
Hirano, K. Yura, L. Li, Y. Yu, H. Ninomiya, M. I. GarcíaꢀMoreno, S.
Ishii, Y. Sakakibara, K. Ohno, E. Nanba, C. Ortiz Mellet, J. M.
García Fernández and Y. Suzuki, Chem. Commun., 2012, 48, 6514;
(e) T. Takai, K. Higaki, M. AguilarꢀMoncayo, T. MenaꢀBarragán, Y.
Hirano, K. Yura, L. Yu, H. Ninomiya, M. I. GarcíaꢀMoreno, Y.
Sakakibara, K. Ohno, E. Nanba, C. Ortiz Mellet, J. M. García
Fernández and Y. Suzuki, Mol.Ther., 2013, 21, 526; (f) H. Suzuki, U.
Ohto, K. Higaki, T. MenaꢀBarragán, M. AguilarꢀMoncayo, C. O.
Mellet, E. Nanba, J. M. García Fernandez, Y. Suzuki and T. Suzuki.
J. Biol. Chem., 2014, 289, 14560.
Currently, the parent NOEV might be replaced by potent Nꢀ
substituted conduramine Fꢀ4 derivatives, which are
conveniently synthesized from (+)ꢀprotoꢀquercitol. Further
studies utilizing chiral conduramine derivatives would deepen
our insight into biochemically interesting aminocyclitols. In
addition, our initial studies suggested that the chaperone effects
were mutation specific6e,7 and many mutants including common
mutations such as R201C are currently listed in βꢀgalactosidase
for GM1ꢀgangliosidosis. Therefore, examining the enhanced
activity spectrum of 3i is particularly important for future
studies. Additional computational calculations and Xꢀray
structure analyses of coꢀcrystallized species will reveal the fine
interactions between the enzyme and the compounds with
atomic precision. We are also interested in preparing and
7
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9
K. Higaki, L. Li, S. Okuzawa, A. Takamuram, K. Yamamoto, K.
Adachi, R. C. Paraquison, T. Takai, H. Ikehata, L. Tominaga, I.
Hisatome, M. Iida, S. Ogawa, J. Matsuda, H. Ninomiya, Y.
Sakakibara, K. Ohno, Y. Suzuki and E. Nanba, Hum. Mutat., 2011,
32, 843.
evaluating the Nꢀcyclohexylmethyl derivatives of valienamines.
Acknowledgements
This study was supported by a MEXT/JPSP KAKENHI grant
and the Takeda Science Foundation. We wish to thank Drs. R.
Sawa and Y. Umezawa at the Institute of Microbial Chemistry
for HRMS analyses.
J. Matsuda, O. Suzuki, A. Oshima, Y. Yamamoto, A. Noguchi, K.
Takimoto, M. Itoh, Y. Matsuzaki, Y. Yasuda, S. Ogawa, Y. Sakata,
E. Nanba, K. Higaki, Y. Ogawa, L. Tominaga, K. Ohno, H. Iwasaki,
H. Watanabe, R. O. Brady and Y. Suzuki, Proc. Natl. Acad. Sci.
USA., 2003, 100, 15912.
Notes and references
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aCentral Research Laboratories, Hokko Chemical Industry, Co., Ltd.,
2165 Toda, Atsugi, 243ꢀ0023 Japan. Eꢀmail: kunoꢀs@hokkochem.co.jp;
Fax: +81ꢀ46ꢀ228ꢀ0164
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bDivision of Functional Genomics, Research Center for Bioscience and
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683ꢀ8503 Japan. Eꢀmail: kh4060@med.tottoriꢀu.ac.jp; Fax: +81ꢀ859ꢀ
386470
cDepartment of Biosciences and Informatics, Faculty of Science and
Technology, Keio University, 3ꢀ14ꢀ1 Hiyoshi, KohokuꢀKu, Yokohama,
223ꢀ8522 Japan.
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