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Johannes M F G Aerts - One of the best experts on this subject based on the ideXlab platform.

  • distinguishing the differences in β glycosylceramidase folds dynamics and actions informs therapeutic uses
    Journal of Lipid Research, 2018
    Co-Authors: Fredj Ben Bdira, Marta Artola, Herman S Overkleeft, Marcellus Ubbink, Johannes M F G Aerts
    Abstract:

    Glycosyl hydrolases (GHs) are carbohydrate-active enzymes that hydrolyze a specific β-glycosidic bond in glycoconjugate substrates; β-glucosidases degrade glucosylceramide, a ubiquitous glycosphingolipid. GHs are grouped into structurally similar families that themselves can be grouped into clans. GH1, GH5, and GH30 glycosidases belong to clan A hydrolases with a catalytic (β/α)8 TIM barrel domain, whereas GH116 belongs to clan O with a catalytic (α/α)6 domain. In humans, GH abnormalities underlie metabolic diseases. The lysosomal enzyme glucocerebrosidase (family GH30), deficient in Gaucher disease and implicated in Parkinson disease etiology, and the cytosol-facing membrane-bound Glucosylceramidase (family GH116) remove the terminal glucose from the ceramide lipid moiety. Here, we compare enzyme differences in fold, action, dynamics, and catalytic domain stabilization by binding site occupancy. We also explore other glycosidases with reported glycosylceramidase activity, including human cytosolic β-glucosidase, intestinal lactase-phlorizin hydrolase, and lysosomal galactosylceramidase. Last, we describe the successful translation of research to practice: recombinant glycosidases and glucosylceramide metabolism modulators are approved drug products (enzyme replacement therapies). Activity-based probes now facilitate the diagnosis of enzyme deficiency and screening for compounds that interact with the catalytic pocket of glycosidases. Future research may deepen the understanding of the functional variety of these enzymes and their therapeutic potential.

  • the development of an aza c glycoside library based on a tandem staudinger aza wittig ugi three component reaction
    European Journal of Organic Chemistry, 2012
    Co-Authors: Johannes M F G Aerts, A Strijland, Richard J B H N Van Den Berg, Tom Wennekes, Kimberley M Bonger, Katrin Vogel, Wilma E Donkerkoopman, Gijsbert A Van Der Marel, Herman S Overkleeft
    Abstract:

    We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries. Variation in the library is achieved by transformation of two pentoses and a hexose into the corresponding 4-azidopentanal and 5-azidohexanal derivatives as precursors for the Staudinger/aza-Wittig process. Further variation is achieved by using different isocyanides as well as protective- and functional-group manipulations on the fully protected Ugi-3CR intermediates. Preliminary biological evaluation of the compound library revealed several low micromolar inhibitors of human acid Glucosylceramidase

  • Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease
    PLOS ONE, 2011
    Co-Authors: Kathleen M Ashe, Jennifer B Nietupski, Mario A. Cabrera-salazar, Christopher G.f. Cooper, Dinesh S Bangari, Lingyun Li, Johannes M F G Aerts, Scott D Bercury, Diane P Copeland
    Abstract:

    The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal Glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.

  • Iminosugar-Based Inhibitors of Glucosylceramide Synthase Increase Brain Glycosphingolipids and Survival in a Mouse Model of Sandhoff Disease
    2011
    Co-Authors: Kathleen M Ashe, Mario A. Cabrera-salazar, Christopher G.f. Cooper, Dinesh S Bangari, Johannes M F G Aerts, Scott D Bercury, Jennifer B, Edward R. Lee, Diane P. Copel
    Abstract:

    The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal Glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reductio

  • identification of the non lysosomal Glucosylceramidase as β glucosidase 2
    Journal of Biological Chemistry, 2007
    Co-Authors: Rolf G Boot, A Strijland, Tom Wennekes, Wilma E Donkerkoopman, Marri Verhoek, Jan Van Marle, Hermen S Overkleeft, Johannes M F G Aerts
    Abstract:

    The primary catabolic pathway for glucosylceramide is catalyzed by the lysosomal enzyme glucocerebrosidase that is defective in Gaucher disease patients. A distinct non-lysosomal Glucosylceramidase has been described but its identity remained enigmatic for years. We here report that the non-lysosomal Glucosylceramidase is identical to the earlier described bile acid β-glucosidase, being β-glucosidase 2 (GBA2). Expressed GBA2 is identical to the native non-lysosomal Glucosylceramidase in various enzymatic features such as substrate specificity and inhibitor sensitivity. Expression of GBA2 coincides with increased non-lysosomal Glucosylceramidase activity, and GBA2-targeted RNA interference reduces endogenous non-lysosomal Glucosylceramidase activity in cells. GBA2 is found to be located at or close to the cell surface, and its activity is linked to sphingomyelin generation. Hydrophobic deoxynojirimycins are extremely potent inhibitors for GBA2. In mice pharmacological inhibition of GBA2 activity is associated with impaired spermatogenesis, a phenomenon also very recently reported for GBA2 knock-out mice (Yildiz, Y., Matern, H., Thompson, B., Allegood, J. C., Warren, R. L., Ramirez, D. M., Hammer, R. E., Hamra, F. K., Matern, S., and Russell, D. W. (2006) J. Clin. Invest. 116, 2985–2994). In conclusion, GBA2 plays a role in cellular glucosylceramide metabolism.

A Strijland - One of the best experts on this subject based on the ideXlab platform.

  • identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase neutral Glucosylceramidase inhibitors
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Amar B T Ghisaidoobe, A Strijland, Wilma E Donkerkoopman, Richard J B H N Van Den Berg, Saleem S Butt, Saskia Scheij, Adrianus M C H Van Den Nieuwendijk, Gerritjan Koomen, Arnold Van Loevezijn, Mark Leemhuis
    Abstract:

    This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral Glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of D-gluco and L-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (D-gluco and L-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted L-ido-configured deoxynojirimycin derivatives are selective for Glucosylceramidase and the nonlysosomal Glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their D-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.

  • Identification and Development of Biphenyl Substituted Iminosugars as Improved Dual Glucosylceramide Synthase/Neutral Glucosylceramidase Inhibitors
    2014
    Co-Authors: Amar T. Ghisaidoobe, A Strijland, Saleem S Butt, Saskia Scheij, Adrianus M C H Van Den Nieuwendijk, Gerritjan Koomen, Arnold Van Loevezijn, Richard J. B. H. N. Van Den Berg, Wilma E. Donker-koopman, Mark Leemhuis
    Abstract:

    This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral Glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of d-gluco and l-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxy­methylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (d-gluco and l-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted l-ido-configured deoxynojirimycin derivatives are selective for Glucosylceramidase and the nonlysosomal Glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their d-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics

  • the development of an aza c glycoside library based on a tandem staudinger aza wittig ugi three component reaction
    European Journal of Organic Chemistry, 2012
    Co-Authors: Johannes M F G Aerts, A Strijland, Richard J B H N Van Den Berg, Tom Wennekes, Kimberley M Bonger, Katrin Vogel, Wilma E Donkerkoopman, Gijsbert A Van Der Marel, Herman S Overkleeft
    Abstract:

    We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries. Variation in the library is achieved by transformation of two pentoses and a hexose into the corresponding 4-azidopentanal and 5-azidohexanal derivatives as precursors for the Staudinger/aza-Wittig process. Further variation is achieved by using different isocyanides as well as protective- and functional-group manipulations on the fully protected Ugi-3CR intermediates. Preliminary biological evaluation of the compound library revealed several low micromolar inhibitors of human acid Glucosylceramidase

  • identification of the non lysosomal Glucosylceramidase as β glucosidase 2
    Journal of Biological Chemistry, 2007
    Co-Authors: Rolf G Boot, A Strijland, Tom Wennekes, Wilma E Donkerkoopman, Marri Verhoek, Jan Van Marle, Hermen S Overkleeft, Johannes M F G Aerts
    Abstract:

    The primary catabolic pathway for glucosylceramide is catalyzed by the lysosomal enzyme glucocerebrosidase that is defective in Gaucher disease patients. A distinct non-lysosomal Glucosylceramidase has been described but its identity remained enigmatic for years. We here report that the non-lysosomal Glucosylceramidase is identical to the earlier described bile acid β-glucosidase, being β-glucosidase 2 (GBA2). Expressed GBA2 is identical to the native non-lysosomal Glucosylceramidase in various enzymatic features such as substrate specificity and inhibitor sensitivity. Expression of GBA2 coincides with increased non-lysosomal Glucosylceramidase activity, and GBA2-targeted RNA interference reduces endogenous non-lysosomal Glucosylceramidase activity in cells. GBA2 is found to be located at or close to the cell surface, and its activity is linked to sphingomyelin generation. Hydrophobic deoxynojirimycins are extremely potent inhibitors for GBA2. In mice pharmacological inhibition of GBA2 activity is associated with impaired spermatogenesis, a phenomenon also very recently reported for GBA2 knock-out mice (Yildiz, Y., Matern, H., Thompson, B., Allegood, J. C., Warren, R. L., Ramirez, D. M., Hammer, R. E., Hamra, F. K., Matern, S., and Russell, D. W. (2006) J. Clin. Invest. 116, 2985–2994). In conclusion, GBA2 plays a role in cellular glucosylceramide metabolism.

  • generation of specific deoxynojirimycin type inhibitors of the non lysosomal Glucosylceramidase
    Journal of Biological Chemistry, 1998
    Co-Authors: Herman S Overkleeft, G H Renkema, J Neele, P Vianello, I O Hung, A Strijland, A M Van Der Burg, G J Koomen, U K Pandit, Johannes M F G Aerts
    Abstract:

    The existence of a non-lysosomal Glucosylceramidase in human cells has been documented (van Weely, S., Brandsma, M., Strijland, A., Tager, J. M., and Aerts, J. M. F. G. (1993) Biochim. Biophys. Acta 1181, 55-62). Hypothetically, the activity of this enzyme, which is localized near the cell surface, may influence ceramide-mediated signaling processes. To obtain insight in the physiological importance of the non-lysosomal Glucosylceramidase, the availability of specific inhibitors would be helpful. Here we report on the generation of hydrophobic deoxynojirimycin (DNM) derivatives that potently inhibit the enzyme. The inhibitors were designed on the basis of the known features of the non-lysosomal Glucosylceramidase and consist of a DNM moiety, an N-alkyl spacer, and a large hydrophobic group that promotes insertion in membranes. In particular, N-(5-adamantane-1-yl-methoxy)pentyl)-DNM is a very powerful inhibitor of the non-lysosomal Glucosylceramidase at nanomolar concentrations. At such concentrations, the lysosomal glucocerebrosidase and alpha-glucosidase, the glucosylceramide synthase, and the N-linked glycan-trimming alpha-glucosidases of the endoplasmic reticulum are not affected.

Amar B T Ghisaidoobe - One of the best experts on this subject based on the ideXlab platform.

  • a fluorescence polarization activity based protein profiling assay in the discovery of potent selective inhibitors for human nonlysosomal Glucosylceramidase
    Journal of the American Chemical Society, 2017
    Co-Authors: Daniel Lahav, Richard J B H N Van Den Berg, Adrianus M C H Van Den Nieuwendijk, Tom Wennekes, Amar B T Ghisaidoobe, Imogen Z Breen, Maria J Ferraz, Liang Wu, Paul P Geurink, Huib Ovaa
    Abstract:

    Human nonlysosomal Glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal Glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recomb...

  • a fluorescence polarization activity based protein profiling assay in the discovery of potent selective inhibitors for human nonlysosomal Glucosylceramidase
    Journal of the American Chemical Society, 2017
    Co-Authors: Daniel Lahav, Imogen Breen, Tom Wennekes, Amar B T Ghisaidoobe, Maria J Ferraz, Chilin Kuo, Richard J B H N Van Den Berg, Adrianus M C H Van Den Nieuwendijk, Bing Liu, Paul P Geurink
    Abstract:

    Human nonlysosomal Glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal Glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.

  • identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase neutral Glucosylceramidase inhibitors
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Amar B T Ghisaidoobe, A Strijland, Wilma E Donkerkoopman, Richard J B H N Van Den Berg, Saleem S Butt, Saskia Scheij, Adrianus M C H Van Den Nieuwendijk, Gerritjan Koomen, Arnold Van Loevezijn, Mark Leemhuis
    Abstract:

    This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral Glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of D-gluco and L-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (D-gluco and L-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted L-ido-configured deoxynojirimycin derivatives are selective for Glucosylceramidase and the nonlysosomal Glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their D-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.

Tom Wennekes - One of the best experts on this subject based on the ideXlab platform.

  • a fluorescence polarization activity based protein profiling assay in the discovery of potent selective inhibitors for human nonlysosomal Glucosylceramidase
    Journal of the American Chemical Society, 2017
    Co-Authors: Daniel Lahav, Richard J B H N Van Den Berg, Adrianus M C H Van Den Nieuwendijk, Tom Wennekes, Amar B T Ghisaidoobe, Imogen Z Breen, Maria J Ferraz, Liang Wu, Paul P Geurink, Huib Ovaa
    Abstract:

    Human nonlysosomal Glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal Glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recomb...

  • a fluorescence polarization activity based protein profiling assay in the discovery of potent selective inhibitors for human nonlysosomal Glucosylceramidase
    Journal of the American Chemical Society, 2017
    Co-Authors: Daniel Lahav, Imogen Breen, Tom Wennekes, Amar B T Ghisaidoobe, Maria J Ferraz, Chilin Kuo, Richard J B H N Van Den Berg, Adrianus M C H Van Den Nieuwendijk, Bing Liu, Paul P Geurink
    Abstract:

    Human nonlysosomal Glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal Glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.

  • A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
    2017
    Co-Authors: Daniël Lahav, Imogen Breen, Tom Wennekes, Maria J Ferraz, Richard J B H N Van Den Berg, Amar T. Ghisaidoobe, Bing Liu, Adrianus M. C. H. Van Den Nieuwendijk, Chilin Kuo
    Abstract:

    Human nonlysosomal Glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal Glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source

  • the development of an aza c glycoside library based on a tandem staudinger aza wittig ugi three component reaction
    European Journal of Organic Chemistry, 2012
    Co-Authors: Johannes M F G Aerts, A Strijland, Richard J B H N Van Den Berg, Tom Wennekes, Kimberley M Bonger, Katrin Vogel, Wilma E Donkerkoopman, Gijsbert A Van Der Marel, Herman S Overkleeft
    Abstract:

    We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries. Variation in the library is achieved by transformation of two pentoses and a hexose into the corresponding 4-azidopentanal and 5-azidohexanal derivatives as precursors for the Staudinger/aza-Wittig process. Further variation is achieved by using different isocyanides as well as protective- and functional-group manipulations on the fully protected Ugi-3CR intermediates. Preliminary biological evaluation of the compound library revealed several low micromolar inhibitors of human acid Glucosylceramidase

  • identification of the non lysosomal Glucosylceramidase as β glucosidase 2
    Journal of Biological Chemistry, 2007
    Co-Authors: Rolf G Boot, A Strijland, Tom Wennekes, Wilma E Donkerkoopman, Marri Verhoek, Jan Van Marle, Hermen S Overkleeft, Johannes M F G Aerts
    Abstract:

    The primary catabolic pathway for glucosylceramide is catalyzed by the lysosomal enzyme glucocerebrosidase that is defective in Gaucher disease patients. A distinct non-lysosomal Glucosylceramidase has been described but its identity remained enigmatic for years. We here report that the non-lysosomal Glucosylceramidase is identical to the earlier described bile acid β-glucosidase, being β-glucosidase 2 (GBA2). Expressed GBA2 is identical to the native non-lysosomal Glucosylceramidase in various enzymatic features such as substrate specificity and inhibitor sensitivity. Expression of GBA2 coincides with increased non-lysosomal Glucosylceramidase activity, and GBA2-targeted RNA interference reduces endogenous non-lysosomal Glucosylceramidase activity in cells. GBA2 is found to be located at or close to the cell surface, and its activity is linked to sphingomyelin generation. Hydrophobic deoxynojirimycins are extremely potent inhibitors for GBA2. In mice pharmacological inhibition of GBA2 activity is associated with impaired spermatogenesis, a phenomenon also very recently reported for GBA2 knock-out mice (Yildiz, Y., Matern, H., Thompson, B., Allegood, J. C., Warren, R. L., Ramirez, D. M., Hammer, R. E., Hamra, F. K., Matern, S., and Russell, D. W. (2006) J. Clin. Invest. 116, 2985–2994). In conclusion, GBA2 plays a role in cellular glucosylceramide metabolism.

Mark Leemhuis - One of the best experts on this subject based on the ideXlab platform.

  • identification and development of biphenyl substituted iminosugars as improved dual glucosylceramide synthase neutral Glucosylceramidase inhibitors
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Amar B T Ghisaidoobe, A Strijland, Wilma E Donkerkoopman, Richard J B H N Van Den Berg, Saleem S Butt, Saskia Scheij, Adrianus M C H Van Den Nieuwendijk, Gerritjan Koomen, Arnold Van Loevezijn, Mark Leemhuis
    Abstract:

    This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral Glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of D-gluco and L-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (D-gluco and L-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted L-ido-configured deoxynojirimycin derivatives are selective for Glucosylceramidase and the nonlysosomal Glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their D-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.

  • Identification and Development of Biphenyl Substituted Iminosugars as Improved Dual Glucosylceramide Synthase/Neutral Glucosylceramidase Inhibitors
    2014
    Co-Authors: Amar T. Ghisaidoobe, A Strijland, Saleem S Butt, Saskia Scheij, Adrianus M C H Van Den Nieuwendijk, Gerritjan Koomen, Arnold Van Loevezijn, Richard J. B. H. N. Van Den Berg, Wilma E. Donker-koopman, Mark Leemhuis
    Abstract:

    This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral Glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of d-gluco and l-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxy­methylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (d-gluco and l-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted l-ido-configured deoxynojirimycin derivatives are selective for Glucosylceramidase and the nonlysosomal Glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their d-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics