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

UN SDGs

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

Access to Document

10.1021/jacs.7b01773

Persistent URL (handle)

Persistent link

Cite this

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

@article{9c3a0a3b421e4b03aa86db855b4c1a5b,

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,

day = "17",

doi = "10.1021/jacs.7b01773",

language = "English",

volume = "139",

pages = "6534--6537",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "19",

}

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

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=85019556343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019556343&partnerID=8YFLogxK

U2 - 10.1021/jacs.7b01773

DO - 10.1021/jacs.7b01773

M3 - Article

C2 - 28463498

AN - SCOPUS:85019556343

SN - 0002-7863

VL - 139

SP - 6534

EP - 6537

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

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this