Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

Ati, Jihen; Lafite, Pierre; Daniellou, Richard

doi:10.3762/bjoc.13.180

Cited by 41 publications

(30 citation statements)

References 75 publications

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“…Native O -glycan structures are sensitive to both chemical and enzymatic hydrolysis in vivo which can limit their oral bioavailability and lifetime in circulation, and subsequently their use in therapeutics. A common strategy used in glycomimetics to improve stability has been to replace the oxygen atom of the glycosidic linkage with a less labile atom or group, such as nitrogen, carbon, sulfur, or selenium [42,43,44,45,46,47,48,49,50,51]. Although these analogues impart enhanced stability, they can also introduce conformational changes which increase the entropic barrier of binding causing losses in affinity; often a desirable balance between stability and activity must be established.…”

Section: Modifications To the O-glycoside Linkagementioning

confidence: 99%

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Hevey

2019

Biomimetics

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The aberrant presentation of carbohydrates has been linked to a number of diseases, such as cancer metastasis and immune dysregulation. These altered glycan structures represent a target for novel therapies by modulating their associated interactions with neighboring cells and molecules. Although these interactions are highly specific, native carbohydrates are characterized by very low affinities and inherently poor pharmacokinetic properties. Glycomimetic compounds, which mimic the structure and function of native glycans, have been successful in producing molecules with improved pharmacokinetic (PK) and pharmacodynamic (PD) features. Several strategies have been developed for glycomimetic design such as ligand pre-organization or reducing polar surface area. A related approach to developing glycomimetics relies on the bioisosteric replacement of carbohydrate functional groups. These changes can offer improvements to both binding affinity (e.g., reduced desolvation costs, enhanced metal chelation) and pharmacokinetic parameters (e.g., improved oral bioavailability). Several examples of bioisosteric modifications to carbohydrates have been reported; this review aims to consolidate them and presents different possibilities for enhancing core interactions in glycomimetics.

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Section: Modifications To the O-glycoside Linkagementioning

confidence: 99%

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Hevey

2019

Biomimetics

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“…In the glycochemistry field, a vast array of carbohydrate-metabolizing enzymes (CAZYmes), including glycoside hydrolases (GH) or glycosyltransferases (GT), has been engineered and used for the chemo-enzymatic synthesis of glycosides [3]. The corresponding methodologies have proved useful in numerous applications ranging from glycosylated natural products to pharmaceuticals [4,5]. However, only few examples in the literature have been describing the use of CAZYmes for the preparation of synthetic thioglycosides that exhibit a sulphur atom linking the glycone and aglycone counterparts instead of more conventional oxygen or nitrogen atoms [6].…”

Section: Introductionmentioning

confidence: 99%

Hydrolysis of Glycosyl Thioimidates by Glycoside Hydrolase Requires Remote Activation for Efficient Activity

et al. 2019

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Chemoenzymatic synthesis of glycosides relies on efficient glycosyl donor substrates able to react rapidly and efficiently, yet with increased stability towards chemical or enzymatic hydrolysis. In this context, glycosyl thioimidates have previously been used as efficient donors, in the case of hydrolysis or thioglycoligation. In both cases, the release of the thioimidoyl aglycone was remotely activated through a protonation driven by a carboxylic residue in the active site of the corresponding enzymes. A recombinant glucosidase (DtGly) from Dictyoglomus themophilum, previously used in biocatalysis, was also able to use such glycosyl thioimidates as substrates. Yet, enzymatic kinetic values analysis, coupled to mutagenesis and in silico modelling of DtGly/substrate complexes demonstrated that the release of the thioimidoyl moiety during catalysis is only driven by its leaving group ability, without the activation of a remote protonation. In the search of efficient glycosyl donors, glycosyl thioimidates are attractive and efficient. Their utility, however, is limited to enzymes able to promote leaving group release by remote activation.

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“…Glycosyltransferases (GTs) (E.C. 2.4.x.x) constitute a large class of enzymes involved in the synthesis of abundant complex glycosidic structures expressed in cells 1 . These glycoconjugates are of upmost importance for the interaction between cells and for infection by pathogenic species 2 .…”

Section: Introductionmentioning

confidence: 99%

The LPG1x family from Leishmania major is constituted of rare eukaryotic galactofuranosyltransferases with unprecedented catalytic properties

Ati

Colas

Lafite

et al. 2018

Sci Rep

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Galactofuranosyltransferases are poorly described enzymes despite their crucial role in the virulence and the pathogenicity of numerous microorganisms. These enzymes are considered as potential targets for therapeutic action. In addition to the only well-characterised prokaryotic GlfT2 from Mycobacterium tuberculosis, four putative genes in Leishmania major were previously described as potential galactofuranosyltransferases. In this study, we have cloned, over-expressed, purified and fully determined the kinetic parameters of these four eukaryotic enzymes, thus demonstrating their unique potency in catalysing the transfer of the galactofuranosyl moiety into acceptors. Their individual promiscuity revealed to be different, as some of them could efficiently use NDP-pyranoses as donor substrates in addition to the natural UDP-galactofuranose. Such results pave the way for the development of chemoenzymatic synthesis of furanosyl-containing glycoconjugates as well as the design of improved drugs against leishmaniasis.

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Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

Cited by 41 publications

References 75 publications

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Hydrolysis of Glycosyl Thioimidates by Glycoside Hydrolase Requires Remote Activation for Efficient Activity

The LPG1x family from Leishmania major is constituted of rare eukaryotic galactofuranosyltransferases with unprecedented catalytic properties

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