Sialidase Inhibitors with Different Mechanisms

Keil, Joseph; Rafn, Garrett R.; Turan, Isaac; Aljohani, Majdi A.; Sahebjam-Atabaki, Reza; Sun, Xue‐Long

doi:10.1021/acs.jmedchem.2c01258

Cited by 22 publications

(12 citation statements)

References 243 publications

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“…We hypothesize that this covalent enzyme–substrate adduct may be occurring through Tyr156 or Tyr162 in the active site. These residues are thought to aid in the generation of an oxocarbenium-like transition state of the donor substrate based on crystallization studies of Cst-II with CMP-3FNeu5Ac. , Covalent enzyme-substrate complexes can occur in sialidase mechanisms, and these Tyr residues, particularly Tyr156, may be close enough in proximity to act as a nucleophile (Figure S14).…”

Section: Resultsmentioning

confidence: 99%

One-Step Selective Labeling of Native Cell Surface Sialoglycans by Exogenous α2,8-Sialylation

Babulic,

Kofsky,

Boddington

et al. 2023

ACS Chem. Biol.

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Exo-enzymatic glycan labeling strategies have emerged as versatile tools for efficient and selective installation of terminal glyco-motifs onto live cell surfaces. Through employing specific enzymes and nucleotide-sugar probes, cells can be equipped with defined glyco-epitopes for modulating cell function or selective visualization and enrichment of glycoconjugates. Here, we identifyCampylobacter jejunisialyltransferase Cst-II I53S as a tool for cell surface glycan modification, expanding the exo-enzymatic labeling toolkit to include installation of α2,8-disialyl epitopes. Labeling with Cst-II was achieved with biotin- and azide-tagged CMP-Neu5Ac derivatives on a model glycoprotein and native sialylated cell surface glycans across a panel of cell lines. The introduction of modified Neu5Ac derivatives onto cells by Cst-II was also retained on the surface for 6 h. By examining the specificity of Cst-II on cell surfaces, it was revealed that the α2,8-sialyltransferase primarily labeled N-glycans, with O-glycans labeled to a lesser extent, and there was an apparent preference for α2,3-linked sialosides on cells. This approach thus broadens the scope of tools for selective exo-enzymatic labeling of native sialylated glycans and is highly amenable for the construction of cell-based arrays.

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Section: Resultsmentioning

confidence: 99%

One-Step Selective Labeling of Native Cell Surface Sialoglycans by Exogenous α2,8-Sialylation

Babulic,

Kofsky,

Boddington

et al. 2023

ACS Chem. Biol.

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“…We further evaluated the capability of our probes for quantitative assessment on the changes of protein glycosylation (Figure S10a). We labeled A549 cells firstly with Ac 4 ManNTfe or/and Ac 4 GalNTfa and subsequently treated them with sialidase (SA, which hydrolyzes and releases sialic acid from glycoproteins) [47] or N ‐Acetyl‐β‐glucosaminidase (NAG, which is responsible for the hydrolysis and discharge of galactosamine or glucosamine from glycoproteins) [48] . 19 F NMR analysis revealed a notable decrease in peak area for Ac 4 ManNTfe‐labeled A549 cells treated with SA compared to those cells without SA treatment (Figure S10b).…”

Section: Resultsmentioning

confidence: 99%

Glycan Metabolic Fluorine Labeling for In Vivo Visualization of Tumor Cells and In Situ Assessment of Glycosylation Variations

Chen,

Lin,

Fan

et al. 2023

Angew Chem Int Ed

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The abnormality in the glycosylation of surface proteins is critical for the growth and metastasis of tumors and their capacity for immunosuppression and drug resistance. This anomaly offers an entry point for real‐time analysis on glycosylation fluctuations. In this study, we report a strategy, glycan metabolic fluorine labeling (MEFLA), for selectively tagging glycans of tumor cells. As a proof of concept, we synthesized two fluorinated unnatural monosaccharides with distinctive 19F chemical shifts (Ac4ManNTfe and Ac4GalNTfa). These two probes could undergo selective uptake by tumor cells and subsequent incorporation into surface glycans. This approach enables efficient and specific 19F labeling of tumor cells, which permits in vivo tracking of tumor cells and in situ assessment of glycosylation changes by 19F MRI. The efficiency and specificity of our probes for labeling tumor cells were verified in vitro with A549 cells. The feasibility of our method was further validated with in vivo experiments on A549 tumor‐bearing mice. Moreover, the capacity of our approach for assessing glycosylation changes of tumor cells was illustrated both in vitro and in vivo. Our studies provide a promising means for visualizing tumor cells in vivo and assessing their glycosylation variations in situ through targeted multiplexed 19F MRI.

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“…The ability of neuraminidase/sialidase inhibitors siastatin B (Kudo et al, 1993; Tailford et al, 2015), N‐acetyl‐2,3‐dehydro‐2‐deoxyneuraminic acid (Magesh et al, 2008), Fv32r (previously also synthesized as 4‐amino‐DANA (Smith et al, 2001)), and the zanamivir precursor zanamivir amine (Caceres et al, 2022) to inhibit Cj0843c suggests that such inhibitors could be starting points for design of more‐potent LT inhibitors. Zanamivir is FDA‐approved to treat flu, and many sialidase inhibitor analogs have previously been synthesized (Keil et al, 2022; Laborda et al, 2016), which could be tested for their ability to inhibit LTs.…”

Section: Discussionmentioning

confidence: 99%

Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of Campylobacter jejuni via targeting different sites with different scaffolds

Kumar

Boorman

Greenlee³

et al. 2023

Protein Science

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Bacterial lytic transglycosylases (LTs) contribute to peptidoglycan cell wall metabolism and are potential drug targets to potentiate β‐lactam antibiotics to overcome antibiotic resistance. Since LT inhibitor development is underexplored, we probed 15 N‐acetyl‐containing heterocycles in a structure‐guided fashion for their ability to inhibit and bind to the Campylobacter jejuni LT Cj0843c. Ten GlcNAc analogs were synthesized with substitutions at the C1 position, with two having an additional modification at the C4 or C6 position. Most of the compounds showed weak inhibition of Cj0843c activity. Compounds with alterations at the C4 position, replacing the ‐OH with a ‐NH2, and C6 position, the addition of a ‐CH3, yielded improved inhibitory efficacy. All 10 GlcNAc analogs were crystallographically analyzed via soaking experiments using Cj0843c crystals and found to bind to the +1 +2 saccharide subsites with one of them additionally binding to the −2 −1 subsite region. We also probed other N‐acetyl‐containing heterocycles and found that sialidase inhibitors N‐acetyl‐2,3‐dehydro‐2‐deoxyneuraminic acid and siastatin B inhibited Cj0843c weakly and crystallographically bound to the −2 −1 subsites. Analogs of the former also showed inhibition and crystallographic binding and included zanamivir amine. This latter set of heterocycles positioned their N‐acetyl group in the −2 subsite with additional moieties interacting in the −1 subsite. Overall, these results could provide novel opportunities for LT inhibition via exploring different subsites and novel scaffolds. The results also increased our mechanistic understanding of Cj0843c regarding peptidoglycan GlcNAc subsite binding preferences and ligand‐dependent modulation of the protonation state of the catalytic E390.

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Sialidase Inhibitors with Different Mechanisms

Cited by 22 publications

References 243 publications

One-Step Selective Labeling of Native Cell Surface Sialoglycans by Exogenous α2,8-Sialylation

One-Step Selective Labeling of Native Cell Surface Sialoglycans by Exogenous α2,8-Sialylation

Glycan Metabolic Fluorine Labeling for In Vivo Visualization of Tumor Cells and In Situ Assessment of Glycosylation Variations

Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of Campylobacter jejuni via targeting different sites with different scaffolds

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