Inhibitor versus chaperone behaviour of d-fagomine, DAB and LAB sp2-iminosugar conjugates against glycosidases: A structure–activity relationship study in Gaucher fibroblasts

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

“…In this sense, it is worth mentioning that although GCase inhibition is generally considered a valuable indication for pharmacological chaperone drug candidates, a higher inhibitory potential does not necessarily translate into better activity enhancement abilities towards the target misfolding mutant enzyme. If displacement of the inhibitor from the enzyme:inhibitor complex is strongly disfavored, the enzyme would not be functional even though the compound may restore the proper folding and trafficking of mutant GCase variants [ 35 ].…”

“…The conversion of the amine-type endocyclic nitrogen of iminosugars into a pseudoamide-type functionality, with high sp 2 -hybridation character (sp 2 -iminosugars) [ 21 , 22 ], has demonstrated to be a very promising strategy to improve both parameters, with several sp 2 -iminosugar representatives under investigational or preclinical development for the LSDs Gaucher [ 23 , 24 , 25 , 26 , 27 ], Fabry [ 28 ], G M1 -gangliosidosis [ 29 , 30 ], and Tay-Sachs diseases [ 31 ]. The glycosidase inhibitory and chaperoning abilities of sp 2 -iminosugars have been found to be strongly dependent on the mono- [ 32 , 33 , 34 , 35 , 36 ] or bicyclic structure of the sugar glycone-like skeleton [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], the configurational pattern [ 45 , 46 , 47 , 48 ], and the nature of nonglycone-type substituents [ 49 , 50 , 51 ]. Differently from classical iminosugars, for which the lability of aminal functionalities prevents the installation of anomeric substituents (except in the case of pseudo- C -glycosides) [ 52 , 53 , 54 , 55 ], sp 2 -iminosugars can bear O -, S -, N -, or C -anomeric aglycone groups while keeping full chemical and configurational stability [ 56 , 57 , 58 , 59 , 60 , ...…”

1,4-Dideoxy-1,4-imino-d-arabinitol (DAB) Analogues Possessing a Hydrazide Imide Moiety as Potent and Selective α-Mannosidase Inhibitors

“… 21 However, it has been shown that selectivity for other glycosidases can be achieved upon chemical modifications. 22 Thus, as part of our ongoing research on sugar hydrazide imides, 23 we wanted to investigate whether the insertion of a hydrazide imide moiety into DAB to obtain arabinohydrazide imides 4 and 5 would have any impact on the inhibition profile as was the case when isofagomine ( 1 ) was converted into its corresponding amidine 2 . In this paper, we present the synthesis of 4 , 5 , and 6 and DFT calculations shedding light on their charge distribution, in addition to their glycosidase inhibitory activity.…”

Structure of a Talaromyces pinophilus GH62 arabinofuranosidase in complex with AraDNJ at 1.25 Å resolution

“…2b), which allows further confirmation of the catalytic apparatus. This compound has found use in studies of other arabinofuranosidases (Axamawaty et al, 1990;Hemsworth et al, 2016) as well as as a scaffold for developing inhibitors of other glycosidases (Siguier et al, 2014;Mena-Barragá n et al, 2016). Azasugars and iminosugars are generally considered to be good inhibitors of retaining glycoside hydrolases by virtue of their endocyclic N atom, which can be protonated, thus mimicking the putative positive charge that is thought to exist in the transition state(s) during glycoside hydrolysis.…”