Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish

Marta Artola; Chi-Lin Kuo; Lindsey T. Lelieveld; Rhianna J. Rowland; Gijsbert A. van der Marel; Jeroen D. C. Codée; Rolf G. Boot; Gideon J. Davies; Johannes M. F. G. Aerts; Herman S. Overkleeft

doi:10.1021/jacs.9b00056

Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish

Marta Artola, Chi-Lin Kuo, Lindsey T. Lelieveld, Rhianna J. Rowland, Gijsbert A. van der Marel, Jeroen D. C. Codée, Rolf G. Boot, Gideon J. Davies, Johannes M. F. G. Aerts, Herman S. Overkleeft

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE), and cyclophellitol. Both compounds, however, also target other retaining glycosidases, rendering generation and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these.

Original language	English
Pages (from-to)	4214–4218
Number of pages	5
Journal	Journal of the American Chemical Society
Volume	141
Issue number	10
Early online date	27 Feb 2019
DOIs	https://doi.org/10.1021/jacs.9b00056
Publication status	Published - 13 Mar 2019

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© 2019 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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© 2019 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
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Artola, M., Kuo, C.-L., Lelieveld, L. T., Rowland, R. J., Marel, G. A. V. D., Codée, J. D. C., Boot, R. G., Davies, G. J., Aerts, J. M. F. G., & Overkleeft, H. S. (2019). Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish. Journal of the American Chemical Society, 141(10), 4214–4218. https://doi.org/10.1021/jacs.9b00056

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title = "Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish",

abstract = "Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE), and cyclophellitol. Both compounds, however, also target other retaining glycosidases, rendering generation and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these.",

author = "Marta Artola and Chi-Lin Kuo and Lelieveld, {Lindsey T.} and Rowland, {Rhianna J.} and Marel, {Gijsbert A. van der} and Cod{\'e}e, {Jeroen D. C.} and Boot, {Rolf G.} and Davies, {Gideon J.} and Aerts, {Johannes M. F. G.} and Overkleeft, {Herman S.}",

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Artola, M, Kuo, C-L, Lelieveld, LT, Rowland, RJ, Marel, GAVD, Codée, JDC, Boot, RG, Davies, GJ, Aerts, JMFG & Overkleeft, HS 2019, 'Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish', Journal of the American Chemical Society, vol. 141, no. 10, pp. 4214–4218. https://doi.org/10.1021/jacs.9b00056

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AU - Artola, Marta

AU - Kuo, Chi-Lin

AU - Lelieveld, Lindsey T.

AU - Rowland, Rhianna J.

AU - Marel, Gijsbert A. van der

AU - Codée, Jeroen D. C.

AU - Boot, Rolf G.

AU - Davies, Gideon J.

AU - Aerts, Johannes M. F. G.

AU - Overkleeft, Herman S.

N1 - © 2019 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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Y1 - 2019/3/13

N2 - Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE), and cyclophellitol. Both compounds, however, also target other retaining glycosidases, rendering generation and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these.

AB - Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson's disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE), and cyclophellitol. Both compounds, however, also target other retaining glycosidases, rendering generation and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these.

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Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish

Abstract

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White Rose Doctoral Training Partnership in Mechanistic Biology and its Strategic Application

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Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish

Abstract

Bibliographical note

Access to Document

Other files and links

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White Rose Doctoral Training Partnership in Mechanistic Biology and its Strategic Application

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