Synthesis of acids as mimetics of 2,3-unsaturated sialic acids for sialidase inhibition

Florio, Pas; Thomson, Robin Joy; Alafaci, Annette; Abo, Samia; Itzstein, Mark von

doi:10.1016/s0960-894x(99)00331-5

Cited by 22 publications

(31 citation statements)

References 17 publications

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“…These results are in good agreement with those of Miyagi et al [3]. Interestingly, at the same concentration, iso-propyl 2-acetamido-2-deoxy-D 4 -b-D D-glucopyranosiduronic acid (5), a Neu5Ac2en mimetic in which the glycerol sidechain of Neu5Ac2en is replaced by an aliphatic ether [37], resulted in ca. 60% inhibition of the sialidase activity.…”

Section: Kinetic Studies Of Rat Cytosolic Sialidasesupporting

confidence: 91%

“…It is clear from this data that the cytosolic sialidase can accommodate hydrophobic groups in the C-6 glycerol binding domain. We have observed a similar hydrophobic group accommodation in microbial sialidases such as V. cholerae sialidase [37,41,42] and influenza virus sialidase [37]. Modest inhibition (18%) was also observed with the a2,3-linked substrate-like compound Neu5Ac-2-S-(a2,3)-Galb1Me 1, a thiosialoside metabolically stable to the action of sialidases [27].…”

Section: +supporting

confidence: 62%

“…The recombinant sialidase activity was inhibited by Neu5Ac2en 4 (95%), a known sialidase inhibitor, and by the previously reported [37] mimetic of Neu5Ac2en, isopropyl 2-acetamido-2-deoxy-D 4 -b-D D-glucopyranosiduronic acid 5 (62%). These compounds are designed to structurally resemble the putative transition state, a sialosyl cation, of the sialidase-catalysed reaction.…”

Section: +mentioning

confidence: 65%

“…These compounds are designed to structurally resemble the putative transition state, a sialosyl cation, of the sialidase-catalysed reaction. We have previously found that 5 inhibits other microbial sialidases such as influenza virus sialidase [37]. It is clear from this data that the cytosolic sialidase can accommodate hydrophobic groups in the C-6 glycerol binding domain.…”

Section: +mentioning

confidence: 69%

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An investigation of the activity of recombinant rat skeletal muscle cytosolic sialidase

et al. 2005

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Rat cytosolic sialidase is expressed at elevated levels in skeletal muscle and is believed to play a role in the myogenic differentiation of muscle cells. Here, we observed varying levels of enhancement of sialidase activity in the presence a range of divalent cations. In particular, a significant enhancement of activity was observed in the presence of Ca 2+ . Conversely, inhibition of the sialidase activity was found when the enzyme was incubated in the presence of Cu 2+ , EDTA, and a range of carbohydrate-based inhibitors. Finally, an investigation of the enzymatic hydrolysis of a synthetic substrate, 4-methylumbelliferyl N-acetyl-a-D D-neuraminide, by 1 H NMR spectroscopy revealed that the reaction catalysed by rat skeletal muscle cytosolic sialidase proceeds with overall retention of anomeric configuration. This result further supports the notion that all sialidases appear to be retaining enzymes.

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Section: Kinetic Studies Of Rat Cytosolic Sialidasesupporting

confidence: 91%

Section: +supporting

confidence: 62%

Section: +mentioning

confidence: 65%

Section: +mentioning

confidence: 69%

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An investigation of the activity of recombinant rat skeletal muscle cytosolic sialidase

et al. 2005

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“…Neuraminidase (Clostridium perfringens Type V), the neuraminidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (ddNeuAc), enzyme substrates, and all reagent-grade chemicals were purchased from Sigma. Two other preparations of neuraminidase inhibitors, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (Neu5Ac2en) and 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid (dgNeu5-Ac2en), were prepared as described previously (32)(33)(34)(35).…”

Section: Methodsmentioning

confidence: 99%

Lysosomal Sialidase (Neuraminidase-1) Is Targeted to the Cell Surface in a Multiprotein Complex That Facilitates Elastic Fiber Assembly

Hinek

Pshezhetsky

Itzstein

et al. 2006

Journal of Biological Chemistry

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146

140

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We have established previously that the 67-kDa elastin-binding protein (EBP), identical to the spliced variant of ␤-galactosidase, acts as a recyclable chaperone that facilitates secretion of tropoelastin. (Hinek, A., Keeley, F. W., and Callahan, J. W. (1995) Exp. Cell Res. 220, 312-324). We now demonstrate that EBP also forms a cell surfacetargeted molecular complex with protective protein/cathepsin A and sialidase (neuraminidase-1), and provide evidence that this sialidase activity is a prerequisite for the subsequent release of tropoelastin. We found that treatment with sialidase inhibitors repressed assembly of elastic fibers in cultures of human skin fibroblasts, aortic smooth muscle cells, and ear cartilage chondrocytes and caused impaired elastogenesis in developing chick embryos. Fibroblasts derived from patients with congenital sialidosis (primary deficiency of neuraminidase-1) and galactosialidosis (secondary deficiency of neuraminidase-1) demonstrated impaired elastogenesis, which could be reversed after their transduction with neuraminidase-1 cDNA or after treatment with bacterial sialidase, which has a similar substrate specificity to human neuraminidase-1. We postulate that neuraminidase-1 catalyzes removal of the terminal sialic acids from carbohydrate chains of microfibrillar glycoproteins and other adjacent matrix glycoconjugates, unmasking their penultimate galactosugars. In turn, the exposed galactosugars interact with the galectin domain of EBP, thereby inducing the release of transported tropoelastin molecules and facilitating their subsequent assembly into elastic fibers.Mature elastic fibers and laminae present in the extracellular matrix of connective tissues of different organs and blood vessel walls are complex structures made of polymeric (insoluble) elastin in which polypeptide chains of tropoelastin are covalently cross-linked and assembled on a scaffold of 12-nm microfibrils consisting of several glycoproteins, e.g. fibrillins and microfibril-associated glycoproteins (1-11). Molecules of monomeric 70-kDa tropoelastin are synthesized by fibroblasts, chondrocytes, and smooth muscle cells and are secreted and properly aligned with one another for the subsequent lysyl oxidase-mediated cross-linking (12). The mechanisms governing tropoelastin secretion and assembly are not fully elucidated. The current data indicate that highly hydrophobic and non-glycosylated tropoelastin associates with several intracellular proteins that chaperone it through the intracellular compartments. Davis et al. (13) documented that, in the ergastoplasmic reticulum, tropoelastin binds to BiP and the peptidylprolyl cis,transisomerase FKPB65. Our immunohistochemical and biochemical studies have indicated that tropoelastin present in endosomal and Golgi compartments is escorted by the 67-kDa elastin-binding protein (EBP) 2 (14, 15), which protects tropoelastin from premature intracellular selfaggregation and an association with serine proteinases (16,17). We have established that, after delivering tropoelastin to...

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N ‐Acetylneuraminic Acid Derivatives and Mimetics as Anti‐Influenza Agents

Thomson¹,

Itzstein²

2003

Carbohydrate‐Based Drug Discovery

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Synthesis of acids as mimetics of 2,3-unsaturated sialic acids for sialidase inhibition

Cited by 22 publications

References 17 publications

An investigation of the activity of recombinant rat skeletal muscle cytosolic sialidase

An investigation of the activity of recombinant rat skeletal muscle cytosolic sialidase

Lysosomal Sialidase (Neuraminidase-1) Is Targeted to the Cell Surface in a Multiprotein Complex That Facilitates Elastic Fiber Assembly

N ‐Acetylneuraminic Acid Derivatives and Mimetics as Anti‐Influenza Agents

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