Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay

Arns, Steve; Tan, Jia; Sun, Sharon; Galey, Adam; Zisman, Natalia; Ross, Fiona C.; Udechukwu, Jenna; Dercho, Samantha; Gusti, Vionarica; Paquette, Jay; Webb, Murray S.; Bourque, Élyse; Withers, Stephen G.; Liggins, Richard

doi:10.1016/j.bmcl.2015.04.059

Cited by 4 publications

(8 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[29] This was then converted into esterified versions to improve cell permeability. Based upon our previous exploration of ester pro-drug versions of modified sialic acids [30], we prepared the ethyl, n-pentyl, and 4-acetoxybenzyl esters at C-1, each in their otherwise per- O -acetylated forms. The effect of per- O -acetylated 8-keto-Neu5Ac esters on polysialic acid expression was assessed in both MCF-7 and AtT-20 cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…We have developed an inhibitor of sialylation that is selective for sialyl glycoforms containing α2,8-linkages rather than the global reduction in sialylation observed with all other reported inhibitors. The type of ester protecting group makes a large difference in the reduction of polySia, suggesting that the limiting step is cytosolic deprotection of the sugar and that improvement in the cytosolic availability of the free sugar may then increase the potency of inhibition, as seen previously in a parallel system [30]. While modification of glycosyl acceptors, generally by methylation or deoxygenation, has been shown to be an effective strategy to inhibit glycosyltransferases in vitro, few such studies have been performed in vivo and to our knowledge, in no case has this involved a ketone substitution.…”

Section: Discussionmentioning

confidence: 96%

“…For example, the role of polySia in immune-mediated cancer cell killing over the course of several days could be investigated. Compound 3, like its di-fluoro-Neu5Ac analog, is likely to have good bioavailability [30], which would facilitate experiments in mice, allowing us to determine the contribution of polySia to various stages of metastasis. In addition to polySia, α2,8-linked Neu5Ac also occurs as part of the b-and c-series gangliosides, which are drug targets for several different types of cancer [44][45][46], suggesting further uses for the reported inhibition strategy.…”

Section: Discussionmentioning

confidence: 99%

“…Synthesis of 8-keto-Neu5Ac derivatives. Per-O-acetylated 8-keto-Neu5Ac esters were synthesized as previously described [29,30] (See SI methods for details). For synthesis of CMP-8-keto-NeuAc, the CMP-Neu5Ac synthetase from Neisseria meningitidis was purified as previously described [36] (See SI methods for details).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Attenuation of polysialic acid biosynthesis in cells by the small molecule inhibitor 8-keto-sialic acid

Hunter

Gao

Chen

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Sialic acids are key mediators of cell function, particularly with regards to cellular interactions with the surrounding environment. Reagents that modulate the display of specific sialyl glycoforms at the cell surface would be useful biochemical tools and potentially allow for therapeutic intervention in numerous challenging chronic diseases. While multiple strategies are being explored for the control of cell surface sialosides, none that shows high selectivity between sialyltransferases or that targets a specific sialyl glycoform has yet to emerge. Here we describe a strategy to block the formation of α2,8–linked sialic acid chains (oligo– and polysialic acid) through the use of 8–keto–sialic acid as a chain–terminating metabolic inhibitor that, if incorporated, can not be elongated. 8–Keto–sialic acid is non–toxic at effective concentrations and serves to block polysialic acid synthesis in cancer cell lines and primary immune cells, with minimal effects on other sialyl glycoforms.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Attenuation of polysialic acid biosynthesis in cells by the small molecule inhibitor 8-keto-sialic acid

Hunter

Gao

Chen

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…29 This was then converted into esterified versions to improve cell permeability. Based upon our previous exploration of ester pro-drug versions of modified sialic acids, 30 we prepared the ethyl, n-pentyl, and 4-acetoxybenzyl esters at C-1, each in their otherwise per-O-acetylated forms. The effect of per-Oacetylated 8-keto-Neu5Ac esters on polysialic acid expression was assessed in both MCF-7 and AtT-20 cancer cell lines.…”

Section: -Keto-neu5ac Derivatives Block Polysialylation Inmentioning

confidence: 99%

Attenuation of Polysialic Acid Biosynthesis in Cells by the Small Molecule Inhibitor 8-Keto-sialic acid

et al. 2022

Self Cite

View full text Add to dashboard Cite

Sialic acids are key mediators of cell function, particularly with regard to cellular interactions with the surrounding environment. Reagents that modulate the display of specific sialyl glycoforms at the cell surface would be useful biochemical tools and potentially allow for therapeutic intervention in numerous challenging chronic diseases. While multiple strategies are being explored for the control of cell surface sialosides, none that shows high selectivity between sialyltransferases or that targets a specific sialyl glycoform has yet to emerge. Here, we describe a strategy to block the formation of α2,8-linked sialic acid chains (oligo-and polysialic acid) through the use of 8-keto-sialic acid as a chain-terminating metabolic inhibitor that, if incorporated, cannot be elongated. 8-Keto-sialic acid is nontoxic at effective concentrations and serves to block polysialic acid synthesis in cancer cell lines and primary immune cells, with minimal effects on other sialyl glycoforms.

show abstract

Discovery of Multi‐Targets Neuraminidase Inhibitor Lead Compound Against Influenza H1N1 Virus A/WSN/33 Based on QSAR, Docking, Dynamics Simulation and Network Pharmacology

Sun

Liu

et al. 2022

ChemistrySelect

View full text Add to dashboard Cite

In this paper, three compounds are discovered as lead compounds of multi‐targets neuraminidase inhibitor drugs against influenza H1N1 virus A/WSN/33 using QSAR, molecular docking, dynamics simulation and network pharmacology. Moreover, NEU1, PLA2G1B and STAT1 are especially related to therapeutic targets of influenza virus. Therefore, the present study can be helpful in the process of the rational drug design of anti‐influenza virus drugs and improve reliability of findings novel multi‐target drugs which may avoid drug‐resistance.

show abstract

Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay

Cited by 4 publications

References 10 publications

Attenuation of polysialic acid biosynthesis in cells by the small molecule inhibitor 8-keto-sialic acid

Attenuation of polysialic acid biosynthesis in cells by the small molecule inhibitor 8-keto-sialic acid

Attenuation of Polysialic Acid Biosynthesis in Cells by the Small Molecule Inhibitor 8-Keto-sialic acid

Discovery of Multi‐Targets Neuraminidase Inhibitor Lead Compound Against Influenza H1N1 Virus A/WSN/33 Based on QSAR, Docking, Dynamics Simulation and Network Pharmacology

Contact Info

Product

Resources

About