Nucleoside triphosphate mimicry: a sugar triazolyl nucleoside as an ATP-competitive inhibitor of B. anthracis pantothenate kinase

Rowan, Andrew S.; Nicely, Nathan I.; Cochrane, Nicola; Wlassoff, Wjatschesslaw A.; Claiborne, Al; Hamilton, Chris J.

doi:10.1039/b909729e

Cited by 47 publications

(37 citation statements)

References 30 publications

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“…Sugar triazolyl fragments and bicyclic oxazolidine rings have been employed in the past to mimic the triphosphate/Mg 2 + side chain that is complexed to different enzymes. [25] Interestingly, some of the obtained derivatives exhibited moderate inhibitory properties.…”

Section: Resultsmentioning

confidence: 99%

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

Matesanz

Dı́az

Corzana

et al. 2012

Chemistry A European J

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The most common mode of bacterial resistance to aminoglycoside antibiotics is the enzyme-catalysed chemical modification of the drug. Over the last two decades, significant efforts in medicinal chemistry have been focused on the design of non- inactivable antibiotics. Unfortunately, this strategy has met with limited success on account of the remarkably wide substrate specificity of aminoglycoside-modifying enzymes. To understand the mechanisms behind substrate promiscuity, we have performed a comprehensive experimental and theoretical analysis of the molecular-recognition processes that lead to antibiotic inactivation by Staphylococcus aureus nucleotidyltransferase 4'(ANT(4')), a clinically relevant protein. According to our results, the ability of this enzyme to inactivate structurally diverse polycationic molecules relies on three specific features of the catalytic region. First, the dominant role of electrostatics in aminoglycoside recognition, in combination with the significant extension of the enzyme anionic regions, confers to the protein/antibiotic complex a highly dynamic character. The motion deduced for the bound antibiotic seem to be essential for the enzyme action and probably provide a mechanism to explore alternative drug inactivation modes. Second, the nucleotide recognition is exclusively mediated by the inorganic fragment. In fact, even inorganic triphosphate can be employed as a substrate. Third, ANT(4') seems to be equipped with a duplicated basic catalyst that is able to promote drug inactivation through different reactive geometries. This particular combination of features explains the enzyme versatility and renders the design of non-inactivable derivatives a challenging task.

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Section: Resultsmentioning

confidence: 99%

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

Matesanz

Dı́az

Corzana

et al. 2012

Chemistry A European J

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“…The Dowex M-4195 resin was purchased from Supelco and subjected to a conditioning treatment. The vinyl sulfone propyl silica gel 5, [28] the aminopropyl silica gel 6, [29] the alkynes 10, [38] 15, [39] 16, [40] 17, [41] 18 [42] and 19, [43] the azides 21, [44] 22, [45] 23, [46] 24, [47] 25, [48] 27, [49] and 28 [50] and the alkyne and azido functionalized silicas [33] used as click scavengers were prepared according to reported procedures in literature. TLCs were performed on Merck Silica Gel 60 F 254 aluminium sheets.…”

Section: Experimental Section Generalmentioning

confidence: 99%

Non‐Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents as Efficient Heterogeneous Catalysts and Copper Scavengers for Click Chemistry

et al. 2010

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Novel supported chelating adsorbents bearing diverse multidentate nitrogenated ligands with strong copper(I) affinities are easily prepared in non-magnetic and magnetic variants using silica and silica-coated magnetite nanoparticles as suitable supports and the aza-Michael-type addition of vinyl sulfones as the ligation tool. These adsorbents are versatile materials with applications in the copper-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry where their complexation abilities enable them to act either as heterogeneous click catalysts when used in their complexed form or as copper(I) scavengers when used in their uncomplexed form. In the first instance, they proved to be robust and efficient heterogeneous catalysts to promote click reactions using extremely low doses and showing negligible copper leaching, particularly in the case of the silica-based non-magnetic adsorbents, allowing a simple operational protocol for their rapid and easy removal by filtration or magnetic decantation and showing good recyclability properties. In their uncomplexed form, the non-magnetic chelating adsorbents are very efficient copper scavengers that are able to remove any traces of metal contamination and that can be applied in tandem with any heterogeneous supported copper(I) catalysts or as standalone copper removing system in any click protocol allowing the isolation of metal-free clicked compounds.

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“…[ 64] A solution of 4 (1.252 g, 3.2 mmol) in a mixture of distilled methanol (50 mL), water (10 mL), and triethylamine (10 mL) was stirred for 16 h at RT. The crude mixture was evaporated and then co-evaporated with toluene three times.…”

Section: -Propynyl B-d-galactopyranosidementioning

confidence: 99%

Synthesis of Dodecavalent Fullerene‐Based Glycoclusters and Evaluation of Their Binding Properties towards a Bacterial Lectin

Cecioni

Oerthel

Iehl

et al. 2011

Chemistry A European J

112

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Multivalency is playing a major role in biological processes and particularly in lectin-carbohydrate interactions. The design of high-affinity ligands of lectins should provide molecules capable of interfering with these biological processes and potentially inhibit bacterial or viral infections. Azide-alkyne "click" chemistry was applied to the synthesis of dodecavalent fullerene-based glycoclusters. The conjugation could be efficiently performed from alkyne or azide functions on either partners (i.e. hexakis-fullerene adduct or glycoside). PA-IL is a bacterial lectin from the opportunistic pathogen Pseudomonas aeruginosa and is involved in the recognition of glycoconjugates on human tissues. The glycoclusters obtained were evaluated as ligands of PA-IL and for their potential for competing with its binding to glycosylated surfaces. The affinities measured by hemagglutination inhibition assay (HIA), enzyme-linked lectin assay (ELLA), and surface plasmon resonance (SPR) displayed a significant "glycoside cluster effect" with up to a 12,000-fold increase in binding when comparing a monovalent carbohydrate reference probe with a dodecavalent fullerene-based glycocluster, albeit with some differences depending on the analytical technique.

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Nucleoside triphosphate mimicry: a sugar triazolyl nucleoside as an ATP-competitive inhibitor of B. anthracis pantothenate kinase

Cited by 47 publications

References 30 publications

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

Non‐Magnetic and Magnetic Supported Copper(I) Chelating Adsorbents as Efficient Heterogeneous Catalysts and Copper Scavengers for Click Chemistry

Synthesis of Dodecavalent Fullerene‐Based Glycoclusters and Evaluation of Their Binding Properties towards a Bacterial Lectin

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