Investigation of original multivalent iminosugars as pharmacological chaperones for the treatment of Gaucher disease

Laigre, Eugénie; Hazelard, Damien; Casas, Josefina; Serra-Vinardell, Jenny; Michelakakis, Helen; Mavridou, Irene; Aerts, Johannes M. F. G.; Delgado, Antonio; Compain, Philippe

doi:10.1016/j.carres.2016.03.007

Cited by 23 publications

(19 citation statements)

References 52 publications

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“…The process of discovering such chemical entities has been largely driven by screening large libraries of compounds or, alternatively, through the rational design of molecules based on the structure and thermodynamics of the target proteins. 1 , 78 , 79 …”

Section: Future Perspectives and Novel Strategiesmentioning

confidence: 99%

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

Pereira

Valentão

2018

Chem. Sci.

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Section: Future Perspectives and Novel Strategiesmentioning

confidence: 99%

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

Pereira

Valentão

2018

Chem. Sci.

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“…Yet, much work is necessary to realize the potential of multivalent enzyme inhibition as a tool in biomedicine: although some preliminary results claimed a certain potential in PC therapies, [66][67][68] previously. 75 For PC treatment, cells were cultured in the medium with or without PCs for 96 h and LAMAN activity in lysates were measured.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperones for the Treatment of α-Mannosidosis

et al. 2019

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α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM causative mutations compromise enzyme folding and could be rescue with purposedesigned pharmacological chaperones (PCs). We found that PCs combining a LAMAN glyconebinding motif based on the 5N,6O-oxomethylidenemannonojirimycin (OMJ) glycomimetic core and different aglycones, in either mono or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation.

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“…Iminosugar clusters already demonstrated their potential on glycosidase inhibition [108][109][110][111], since an increase in the inhibition potency, as well as an improvement in the enzymatic selectivity, was observed as a result of multivalency [108,[112][113][114][115]. Accordingly, several iminosugar click clusters with valencies ranging from 3 to 14, previously tested as glycosidase inhibitors [116][117][118] and pharmacological chaperones for the treatment of lysosomal storage diseases [119,120], were evaluated as CFTR correctors ( Figure 8) [106]. Two classes of compounds having different valencies and alkyl spacer lengths (C6 or C9) were considered: tri-and tetravalent derivatives 31-32, built on a penta-erythritol, and hepta-and tetra-decavalent iminosugar-based cyclodextrins 33-34.…”

Section: Iminosugar Click Clusters: Multivalent Effect On the Rescue mentioning

confidence: 99%

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Esposito

D’Alonzo

Fenza

et al. 2020

IJMS

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Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

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Investigation of original multivalent iminosugars as pharmacological chaperones for the treatment of Gaucher disease

Cited by 23 publications

References 52 publications

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones

Pharmacological Chaperones for the Treatment of α-Mannosidosis

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

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