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

Abstract

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.

Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

“…Although in our in vitro study we employed the 3-Fax sialic acid analog that inhibits virtually all sialyltransferases [ 37 , 41 ], we should consider that the use of this compound in vivo may have some limitations, at least if systemically administered, because of deleterious effects on liver and kidney function [ 40 ]. Therefore, exploiting more selective sialyltransferase inhibitors such as 8-keto-Neu5Ac, which was found to be nontoxic at effective concentrations and to block polySia synthesis in cancer cell lines with minimal effects on other sialyl glycoforms [ 37 , 60 ], is advisable for future in vivo experimentation. Finally, we acknowledge that, following the herein demonstration of the ability of sialylation blockade to prevent fibroblast-to-myofibroblast transition, further work is necessary to demonstrate whether the same approach might also be effective in inducing myofibroblast dedifferentiation and skin fibrosis regression.…”