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Targeting Galectins With Glycomimetics.

ABSTRACT: Among glycan-binding proteins, galectins, ?-galactoside-binding lectins, exhibit relevant biological roles and are implicated in many diseases, such as cancer and inflammation. Their involvement in crucial pathologies makes them interesting targets for drug discovery. In this review, we gather the last approaches toward the specific design of glycomimetics as potential drugs against galectins. Different approaches, either using specific glycomimetic molecules decorated with key functional groups or employing multivalent presentations of lactose and N-acetyl lactosamine analogs, have provided promising results for binding and modulating different galectins. The review highlights the results obtained with these approximations, from the employment of S-glycosyl compounds to peptidomimetics and multivalent glycopolymers, mostly employed to recognize and/or detect hGal-1 and hGal-3.

SUBMITTER: Bertuzzi S

PROVIDER: S-EPMC7426508 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Targeting Galectins With Glycomimetics.

Bertuzzi Sara S Quintana Jon I JI Ardá Ana A Gimeno Ana A Jiménez-Barbero Jesús J

Frontiers in chemistry 20200807

Among glycan-binding proteins, galectins, β-galactoside-binding lectins, exhibit relevant biological roles and are implicated in many diseases, such as cancer and inflammation. Their involvement in crucial pathologies makes them interesting targets for drug discovery. In this review, we gather the last approaches toward the specific design of glycomimetics as potential drugs against galectins. Different approaches, either using specific glycomimetic molecules decorated with key functional groups ...[more]

PMID: 32850631

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Project description:BackgroundGlycosidases are involved in several metabolic pathways and the development of inhibitors is an important challenge towards the treatment of diseases, such as diabetes, cancer and viral infections including AIDS. Thus, inhibition of intestinal alpha-glucosidases can be used to treat diabetes through the lowering of blood glucose levels, and alpha-glucosidase inhibitors are being marketed against type 2 (non-insulinodependent mellitus) diabetes (i.e.: Glyset or Diastabol, Basen and Glucor or Precose).ResultsIn that context, new C8-carbasugars and related aminocyclitols have been targeted in order to study the effect of the enhanced flexibility and of the new spatial distribution displayed by these structures on their adaptability in the active site of the enzymes. The synthesis of these new C8-glycomimetics is described from enantiomerically pure C2-symmetrical polyhydroxylated cyclooctenes. Their obtention notably involved a syn-dihydroxylation, and more extended functionalization through formation of a cis-cyclic sulfate followed by amination and subsequent reductive amination. This strategy involving the nucleophilic opening of a cis-cyclic sulfate by sodium azide is to our knowledge the first example in C8-series. It revealead to be an efficient alternative to the nucleoplilic opening of an epoxide moiety which proved unsuccessful in this particular case, due to the hindered conformation of such epoxides as demonstrated by X-ray cristallographic analysis.ConclusionThe biological activity of the synthesized glycomimetics has been evaluated towards 24 commercially available glycosidases. The weak observed activities can probably be related to the spatial disposition of the hydroxy and amino groups which depart too much from that realized in glycomimetics such as valiolamine, voglibose and valienamine. Nevertheless, the synthetic strategy described here is efficient and general, and could be extended to increase the diversity of the glycosidase inhibitors obtained since this diversity is introduced in an ultimate step of the synthesis.

Dataset Information

Targeting Galectins With Glycomimetics.

Publications

Targeting Galectins With Glycomimetics.

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