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

Kris Dammen-Brower; Olivia Arbogast; Stanley Zhu; Chunfang Qiu; Cissy Zhang; Pratik Khare; Anne Le; Xiaofeng Jia; Kevin J Yarema

doi:10.1016/j.bioadv.2024.214144

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

Biomater Adv. 2024 Dec 7:169:214144. doi: 10.1016/j.bioadv.2024.214144. Online ahead of print.

Authors

Kris Dammen-Brower¹, Olivia Arbogast¹, Stanley Zhu¹, Chunfang Qiu², Cissy Zhang³, Pratik Khare³, Anne Le⁴, Xiaofeng Jia⁵, Kevin J Yarema⁶

Affiliations

¹ Department of Biomedical Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Whiting School of Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.
² Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA; Gigantest Inc, 31 Light Street, Baltimore, MD, USA.
⁴ Gigantest Inc, 31 Light Street, Baltimore, MD, USA.
⁵ Department of Biomedical Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, USA; Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, MD, USA; Department of Orthopedics, School of Medicine, University of Maryland, Baltimore, MD, USA; Department of Anatomy and Neurobiology, School of Medicine, University of Maryland, Baltimore, MD, USA. Electronic address: xjia@som.umaryland.edu.
⁶ Department of Biomedical Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Whiting School of Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address: kyarema1@jhu.edu.

PMID: 39754871
DOI: 10.1016/j.bioadv.2024.214144

Abstract

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 brain injury by upregulation of anti-inflammatory metabolites (e.g., α- & γ-linolenic acids) valuable for dampening injury- and treatment-related inflammation. Finally, these analogs modulate compounds that control proline (e.g., 1-pyrroline-2-carboxylate), a master regulator of many cellular activities. Overall, this study presents new mechanisms and pathways to exploit metabolic glycoengineering for neural repair and treatment of neurodegenerative diseases.

Keywords: Alkyl-modified sialic acids; ManNAc analogs; Metabolic glycoengineering; Neural stem cells; Stem cell metabolism; Thiol-modified sialic acids.