Abstract
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.
Highlights
After the isolation from bacteria (Streptomyces) of the first natural iminosugar, nojirimycin (NJ, 1) [2], the chemical synthesis and isolation from mulberry of deoxynojirimycin (DNJ, 2) [3], a potent αand β-glucosidase inhibitor [4], opened the way to the advent of this new class of glycomimetics
Attention has been focused on the trafficking defect of F508del-CFTR, whose correction may be achieved through direct modulation of the protein folding or acting on enzymes involved in the protein proteostasis pathway [46,60,67]
Concluding Remarks Iminosugars represent the most important class of glycomimetics, showing high pharmacological potenItmiailnoinsusgeavrseralretphreersaepnet uttihcefiemldoss, t asimaporerstaunltt ocflatshseirofexcgellylecnotmaimbieltiticys,toshinotweriancgt whiitghh cpahrbaormhyadcoraloteg-ipcarol cpeostseinntgialeinnzysemveesra. l tOhevrearpethueticlafsietldyse,aarss,atrheessueltporfotpheerirtieexschelalevnet baebeilnityaptopilnietderatoct dwevitehlocpardbiovheyrsdertahtee-rpaproecuetsicsianpgperonazcyhmesesf.oOr tvheerttrheaetmlasetntyeoaf rCs,F,thexepselopitrionpgetrhteieisnvhoalvveembeeennt oapf spplieecdifitco glycosidases in biological processes which are relevant in the pathogenesis of cystic fibrosis (CF)
Summary
Whether of natural (from plant or microbial world) or synthetic origin, iminosugars contain a wide variety of small organic molecules belonging to the class of pyrrolidines, piperidines, azepanes, nortropanes, pyrrolizidines and indolizidines (Figure 1) [1]. After the isolation from bacteria (Streptomyces) of the first natural iminosugar, nojirimycin (NJ, 1) [2], the chemical synthesis and isolation from mulberry of deoxynojirimycin (DNJ, 2) [3], a potent α- and β-glucosidase inhibitor [4], opened the way to the advent of this new class of glycomimetics In their simplest structure, they typically mimic the corresponding furanose or pyranose monosaccharide skeleton by replacement of endocyclic oxygen with an amino function, resembling carbohydrate substrates or saccharide hydrolysis transition states (Figure 2) [5,6,7]. Issues related to competitive inhibition can be overcome with iminosugars acting as allosteric or nonactive site binders able to stabilize mutant proteins and promote ER trafficking, allowing at the same time simplified administration procedures and an increase in enzyme activity [43] This approach has found some successful applications in lysosomal rare disease pharmacological treatments [44,45]. Over the last decade, iminosugar therapeutic potential has been evaluated in the management of another rare disease, cystic fibrosis
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