Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Thomas J.M. Beenakker; Dennis P.A. Wander; Wendy A. Offen; Marta Artola; Lluís Raich; Maria J. Ferraz; Kah Yee Li; Judith H.P.M. Houben; Erwin R. Van Rijssel; Thomas Hansen; Gijsbert A. Van Der Marel; Jeroen D.C. Codée; Johannes M.F.G. Aerts; Carme Rovira; Gideon J. Davies; Herman S. Overkleeft

doi:10.1021/jacs.7b01773

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Thomas J.M. Beenakker
, Dennis P.A. Wander
, Wendy A. Offen
, Marta Artola
, Lluís Raich
, Maria J. Ferraz
, Kah Yee Li
, Judith H.P.M. Houben
, Erwin R. Van Rijssel
, Thomas Hansen
, Gijsbert A. Van Der Marel
, Jeroen D.C. Codée
, Johannes M.F.G. Aerts
, Carme Rovira
, Gideon J. Davies^*
, Herman S. Overkleeft

^*Corresponding author for this work

Chemistry and Pharmaceutical Sciences

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine - both covalent retaining β-glucosidase inhibitors - we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the ⁴H₃ transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the ⁴H₃ conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (K_i = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the ⁴H₃ conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

Original language	English
Pages (from-to)	6534-6537
Number of pages	4
Journal	Journal of the American Chemical Society
Volume	139
Issue number	19
DOIs	https://doi.org/10.1021/jacs.7b01773
Publication status	Published - 17 May 2017

Funding

We thank The Netherlands Organization for Scientific Research (NWO-CW, ChemThem grant to J.M.A. and H.S.O.), the European Research Council (ERC-2011-AdG-290836 Chembiosphing to H.S.O., and ERC-2012-AdG-32294 Glycopoise to G.J.D.), the Spanish Ministry of Economy and Competitiveness (CTQ2014-55174-P to C.R.), and the Generalitat de Catalunya (2014SGR-987 to C.R.) for financial support. L.R. thanks the University of Barcelona for an APIF predoctoral fellowship.

Funders	Funder number
NWO-CW
ERC-2011-AdG-290836 Chembiosphing
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
ERC-2012-AdG-32294 Glycopoise
APIF
European Commission
Universitat de Barcelona
European Research Council
Generalitat de Catalunya	2014SGR-987
Ministerio de Economía y Competitividad	CTQ2014-55174-P
Seventh Framework Programme	290836

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 14 Life Below Water

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Beenakker, T. J. M., Wander, D. P. A., Offen, W. A., Artola, M., Raich, L., Ferraz, M. J., Li, K. Y., Houben, J. H. P. M., Van Rijssel, E. R., Hansen, T., Van Der Marel, G. A., Codée, J. D. C., Aerts, J. M. F. G., Rovira, C., Davies, G. J., & Overkleeft, H. S. (2017). Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors. Journal of the American Chemical Society, 139(19), 6534-6537. https://doi.org/10.1021/jacs.7b01773

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title = "Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors",

abstract = "The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine - both covalent retaining β-glucosidase inhibitors - we postulated that the corresponding carba {"}cyclopropyl{"} analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.",

author = "Beenakker, \{Thomas J.M.\} and Wander, \{Dennis P.A.\} and Offen, \{Wendy A.\} and Marta Artola and Llu{\'i}s Raich and Ferraz, \{Maria J.\} and Li, \{Kah Yee\} and Houben, \{Judith H.P.M.\} and \{Van Rijssel\}, \{Erwin R.\} and Thomas Hansen and \{Van Der Marel\}, \{Gijsbert A.\} and Cod{\'e}e, \{Jeroen D.C.\} and Aerts, \{Johannes M.F.G.\} and Carme Rovira and Davies, \{Gideon J.\} and Overkleeft, \{Herman S.\}",

year = "2017",

month = may,

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doi = "10.1021/jacs.7b01773",

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Beenakker, TJM, Wander, DPA, Offen, WA, Artola, M, Raich, L, Ferraz, MJ, Li, KY, Houben, JHPM, Van Rijssel, ER, Hansen, T, Van Der Marel, GA, Codée, JDC, Aerts, JMFG, Rovira, C, Davies, GJ & Overkleeft, HS 2017, 'Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors', Journal of the American Chemical Society, vol. 139, no. 19, pp. 6534-6537. https://doi.org/10.1021/jacs.7b01773

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T1 - Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

AU - Beenakker, Thomas J.M.

AU - Wander, Dennis P.A.

AU - Offen, Wendy A.

AU - Artola, Marta

AU - Raich, Lluís

AU - Ferraz, Maria J.

AU - Li, Kah Yee

AU - Houben, Judith H.P.M.

AU - Van Rijssel, Erwin R.

AU - Hansen, Thomas

AU - Van Der Marel, Gijsbert A.

AU - Codée, Jeroen D.C.

AU - Aerts, Johannes M.F.G.

AU - Rovira, Carme

AU - Davies, Gideon J.

AU - Overkleeft, Herman S.

PY - 2017/5/17

Y1 - 2017/5/17

N2 - The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine - both covalent retaining β-glucosidase inhibitors - we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

AB - The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine - both covalent retaining β-glucosidase inhibitors - we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

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AN - SCOPUS:85019556343

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JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 19

ER -

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Abstract

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UN SDGs

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