Carbohydrate–Neuroactive Hybrid Strategy for Metabolic Glycan Engineering of the Central Nervous System in Vivo

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• 作者：Asif Shajahan ; Shubham Parashar ; Surbhi Goswami ; Syed Meheboob Ahmed ; Perumal NagarajanSrinivasa-Gopalan Sampathkumar
• 刊名：Journal of the American Chemical Society
• 出版年：2017
• 出版时间：January 18, 2017
• 年：2017
• 卷：139
• 期：2
• 页码：693-700
• 全文大小：527K
• ISSN：1520-5126

文摘

Sialic acids are abundant in the central nervous system (CNS) and are essential for brain development, learning, and memory. Dysregulation in biosynthesis of sialo-glycoconjugates is known to be associated with neurological disorders, CNS injury, and brain cancer. Metabolic glycan engineering (MGE) and bioorthogonal ligation have enabled study of biological roles of glycans in vivo; however, direct investigations of sialoglycans in brain have been intractable. We report a simple strategy utilizing carbohydrate–neuroactive hybrid (CNH) molecules, which exploit carrier-mediated transport systems available at the blood–brain barrier, to access brain via tail vein injection in mice. Peracetylated N-azidoacetyl-d-mannosamine (Ac₄ManNAz) conjugated with neuroactive carriers, namely, nicotinic acid, valproic acid, theophylline-7-acetic acid, and choline, were synthesized and evaluated in SH-SY5Y (human neuroblastoma) cells for MGE. Intravenous administration of CNH molecules in mice (C57BL/6J and BALB/cByJ) resulted in robust expression of N-azidoacetyl-neuraminic acid (NeuAz)-carrying glycoproteins in both brain and heart, while the nonhybrid molecule Ac₄ManNAz showed NeuAz expression in heart but not in brain. Successful neuroactive carriers were then conjugated with N-butanoyl-d-mannosamine (ManNBut) with a goal to achieve modulation of polysialic acid (polySia) on neural cell adhesion molecules (NCAM). PolySia levels on NCAM in adult mice were reduced significantly upon administration of Ac₃ManNBut-nicotinate hybrid, but not with Ac₄ManNBut. This novel application of MGE not only offers a noninvasive tool for investigating brain glycosylation, which could be developed in to brain mapping applications, but also serves as a potential drug by which modulation of neural glycan biosynthesis and thus function can be achieved in vivo.