Tailored chondroitin sulfate glycomimetics via a tunable multivalent scaffold for potentiating NGF/TrkA-induced neurogenesis.
نویسندگان
چکیده
The challenges inherent in the synthesis of large glycosaminoglycan (GAG) polysaccharides have made chemically accessible multivalent glycoligands a valuable tool in the field of GAG mimetics. However, the difficulty of positioning sulfated sugar motifs at desired sites has hindered efforts to precisely tailor their biofunctions. Here, we achieved precise orientation of sulfated disaccharide motifs by taking advantage of a structurally well-defined polyproline scaffold, and describe systematic explorations into the importance of the spatial arrangement of sulfated sugars along the scaffold backbone in designing multivalent glycoligands. Our protein binding studies demonstrate that the specific conformational display of pendant sugars is central to direct their multivalent interactions with NGF. By employing computational modeling and cellular studies, we have further applied this approach to engineer NGF-mediated signaling by regulating the NGF/TrkA complexation process, leading to enhanced neuronal differentiation and neurite outgrowth of PC12 cells. Our findings offer a promising strategy for the pinpoint engineering of GAG-mediated biological processes and a novel method of designing new therapeutic agents that are highly specific to GAG-associated disease.
منابع مشابه
Tailored chondroitin sulfate glycomimetics via a tunable multivalent scaffold for potentiating NGF/TrkA-induced neurogenesis† †Electronic supplementary information (ESI) available: Detailed synthesis of CS disaccharides including 1H, 13C NMR, and mass data, general peptide synthesis, click reaction including FT-IR spectra of polyprolines and glycopeptides, procedures for CD measurements including spectra of glycopeptide 1–7, ELISA and SPR measurements including complete kinetic parameters, computational methods including predicted glycopeptide binding sites on the NGF/TrkA complex in table, cellular assays and immunohistochemistry are described. See DOI: 10.1039/c4sc02553a Click here for additional data file.
General Methods Unless otherwise stated, reactions were performed in flame-dried glassware under argon atmosphere and using anhydrous solvents. All commercially obtained reagents were used as received unless otherwise noted. Thin layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm). Visualization of the developed chromatogram was performed by UV,...
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متن کاملAMACHER, Jeanine
Page 1 Extensive neuronal networks coordinate crucial processes within the human body. One of the key players in neuronal growth and differentiation, nerve growth factor (NGF), was discovered in the early 1950s [1]. Forty years later, an interaction between NGF and a tyrosine receptor kinase, TrkA, was identified [2-4]. The neurotrophic effects of NGF are initiated through its activation of Tr...
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ورودعنوان ژورنال:
- Chemical science
دوره 6 1 شماره
صفحات -
تاریخ انتشار 2015