Examining structure-activity relationships of ManNAc analogs used in the metabolic glycoengineering of human neural stem cells

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

This study defines biochemical mechanisms that contribute to novel neural-regenerative activities we recently demonstrated for thiol-modified ManNAc analogs in human neural stem cells (hNSCs) by comparing our lead drug candidate for brain repair, "TProp," to a "size-matched" N-alkyl control analog, "But." These analogs biosynthetically install non-natural sialic acids into cell surface glycans, altering cell surface receptor activity and adhesive properties of cells. In this study, TProp modulated sialic acid-related biology in hNSCs to promote neuronal differentiation through modulation of cell adhesion molecules (integrins α6, β1, E-cadherin, and PSGL-1) and stem cell markers. By comparison, But elicited minimal change to these endpoints, indicating dependence on the chemical properties of the thiol group of non-natural sialic acids and not the size of this sugar's N-acyl group. Conversely, But elicited distinct intracellular responses including increased nestin expression (~6-fold) and the modulation of several metabolites identified through cell-wide screening. Metabolites up-regulated by But included dopamine and norfenenfrine, suggesting that this analog may be a drug candidate for treating neural damage associated with conditions such as Parkinson's disease. The metabolomics data also provided new insights into the neuroprotective effects of TProp when used to treat brai

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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