Multivalent iminosugars to modulate affinity and selectivity for glycosidases

Diot, Jennifer D.; García‐Moreno, M. Isabel; Gouin, Sébastien G.; Mellet, Carmen Ortiz; Haupt, Karsten; Kovensky, José

doi:10.1039/b815408b

Cited by 116 publications

(117 citation statements)

References 29 publications

(25 reference statements)

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“…[24] Furthermore, numerous recent examples successfully report the use of CuAAC to design glycoclusters and other sugar mimetics. [25,26] Compound 2 was obtained in three synthetic steps as previously described in the literature (Scheme 2). [27] Tosylation of unprotected glucose in the C-6 position followed by acetylation of the hydroxyl groups and substitution by an azide efficiently provided gram-scale quantities of 2.…”

Section: Resultsmentioning

confidence: 99%

Clustering of Escherichia coli Type‐1 Fimbrial Adhesins by Using Multimeric Heptyl α‐D‐Mannoside Probes with a Carbohydrate Core

Almant

Moreau

Kovensky

et al. 2011

Chemistry A European J

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Heptyl α-D-mannoside (HM) is a strong inhibitor of the FimH lectin that mediates the initial adhesion of the uropathogenic Escherichia coli (E. coli) to the bladder cells. We designed a set of multivalent HM ligands based on carbohydrate cores with structural valencies that range from 1 to 7. The chemical strategy used to construct the regular hydrophilic structures consisted of the repetition of a critical glucoside fragment. A primary amino group was grafted at the sugar reducing end to couple the multimers to a fluorescent label. A one-pot synthetic approach was developed to tether the ligands and the fluorescein isothiocyanate (FITC) probe to the scaffold simultaneously. Isothermal calorimetry with the monomeric FimH lectin revealed nanomolar affinities and saturation of all structurally available binding sites on the multivalent HM ligands. Direct titrations domain showed almost strict correlation of enthalpy-entropy compensation with increasing valency of the ligand, whereas reverse titration calorimetry demonstrated negative cooperativity between the first and the second binding site of the divalent heptyl mannoside. A multivalency effect was nevertheless observed by inhibiting the haemagglutination of type-1 piliated UTI89 E. coli, with a titer as low as 60 nM for the heptavalent HM ligand. An FITC-labeled HM trimer showed capture and cross-linking of living bacteria in solution, a phenomenon not previously described with low-valency ligands.

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Section: Resultsmentioning

confidence: 99%

Clustering of Escherichia coli Type‐1 Fimbrial Adhesins by Using Multimeric Heptyl α‐D‐Mannoside Probes with a Carbohydrate Core

Almant

Moreau

Kovensky

et al. 2011

Chemistry A European J

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“…[36] More recently, Compain and Nierengarten described a fullerene iminosugar ball that was assayed against a range of glycosidases and displayed a relative inhibition potency of 179 compared with the monomeric structure, also against Jack bean a-mannosidase. [9] These literature data clearly indicate that all enzymes are not prone to multivalent inhibition and that the nature of both the central core structure and the spacer unit tethering the inhibitory monomers play critical roles in the inhibition process.…”

Section: Inhibition Of Waacmentioning

confidence: 99%

The Inhibition of Liposaccharide Heptosyltransferase WaaC with Multivalent Glycosylated Fullerenes: A New Mode of Glycosyltransferase Inhibition

Durka

Buffet

Iehl

et al. 2011

Chemistry A European J

101

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L,D-Heptosides (L-glycero-D-manno-heptopyranoses) are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development of novel antibacterial agents. This work describes the synthesis of a series of fullerene hexa-adducts bearing 12 copies of peripheral sugars displaying the mannopyranose core structure of bacterial L,D-heptoside. The multimers were assembled through an efficient copper-catalyzed alkyne-azide cycloaddition reaction as the final step. The final fullerene sugar balls were assayed as inhibitors of heptosyltransferase WaaC, the glycosyltransferase catalyzing the incorporation of the first L-heptose into LPS. Interestingly, the inhibition of the final molecules was found in the low micromolar range (IC(50) =7-45 μM), whereas the corresponding monomeric glycosides displayed high micromolar to low millimolar inhibition levels (IC(50) always above 400 μM). When evaluated on a "per-sugar" basis, these inhibition data showed that, in each case, the average affinity of a single glycoside of the fullerenes towards WaaC was significantly enhanced when displayed as a multimer, thus demonstrating an unexpected multivalent effect. To date, such a multivalent mode of inhibition had never been evidenced with glycosyltransferases.

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“…These scaffolds have been successfully used recently for the design of multimeric glycoclusters. [9,10] Divalent glycoconjugate 3 was designed to evaluate the extend to which the nature of the core could influence the binding affinity for FimH. The efficient CuAAC, in terms of conversion and selectivity, was implemented to tether alkynyl armed heptyl mannosides to azide functionalized EG.…”

Section: Synthesismentioning

confidence: 99%

Synthetic Multimeric Heptyl Mannosides as Potent Antiadhesives of Uropathogenic Escherichia coli

et al. 2009

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Urinary tract infections caused by uropathogenic Escherichia coli presents a serious communal and nosocomial health problem initiated by bacterial adhesion to the bladder cells. E. coli expresses fimbriae with a mannose-binding adhesin, FimH, at the tip. Heptyl alpha-D-mannoside (HM) is a nanomolar inhibitor of this lectin, preventing adhesion of type 1-piliated E. coli and reducing bacteria levels in a murine cystitis model. Herein, we described the synthesis of multimeric heptyl-mannosides with valencies ranging from one to four by copper-catalyzed azide alkyne cycloaddition (CuAAC). Biological evaluation of the multivalent compounds revealed an increase in potency compared to HM. Inhibition of bladder cell binding highlighted a promising tetravalent derivative with inhibitory concentrations 6000- and 64-fold lower than mannose and HM respectively.

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Multivalent iminosugars to modulate affinity and selectivity for glycosidases

Cited by 116 publications

References 29 publications

Clustering of Escherichia coli Type‐1 Fimbrial Adhesins by Using Multimeric Heptyl α‐D‐Mannoside Probes with a Carbohydrate Core

Clustering of Escherichia coli Type‐1 Fimbrial Adhesins by Using Multimeric Heptyl α‐D‐Mannoside Probes with a Carbohydrate Core

The Inhibition of Liposaccharide Heptosyltransferase WaaC with Multivalent Glycosylated Fullerenes: A New Mode of Glycosyltransferase Inhibition

Synthetic Multimeric Heptyl Mannosides as Potent Antiadhesives of Uropathogenic Escherichia coli

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