Mimicking Neuroligin-2 Functions in β-Cells by Functionalized Nanoparticles as a Novel Approach for Antidiabetic Therapy

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• 作者：Anna Munder ; Liron L. Israel ; Shirin Kahremany ; Rina Ben-Shabat-Binyamini ; Charles Zhang ; Michal Kolitz-Domb ; Olga Viskind ; Anna Levine ; Hanoch Senderowitz ; Steven Chessler ; Jean-Paul Lellouche ; Arie Gruzman
• 刊名：ACS Applied Materials & Interfaces
• 出版年：2017
• 出版时间：January 18, 2017
• 年：2017
• 卷：9
• 期：2
• 页码：1189-1206
• 全文大小：1135K
• ISSN：1944-8252

文摘

Both pancreatic β-cell membranes and presynaptic active zones of neurons include in their structures similar protein complexes, which are responsible for mediating the secretion of bioactive molecules. In addition, these membrane-anchored proteins regulate interactions between neurons and guide the formation and maturation of synapses. These proteins include the neuroligins (e.g., NL-2) and their binding partners, the neurexins. The insulin secretion and maturation of β-cells is known to depend on their 3-dimensional (3D) arrangement. It was also reported that both insulin secretion and the proliferation rates of β-cells increase when cells are cocultured with clusters of NL-2. Use of full-length NL-2 or even its exocellular domain as potential β-cell functional enhancers is limited by the biostability and bioavailability issues common to all protein-based therapeutics. Thus, based on molecular modeling approaches, a short peptide with the potential ability to bind neurexins was derived from the NL-2 sequence. Here, we show that the NL-2-derived peptide conjugates onto innovative functional maghemite (γ-Fe₂O₃)-based nanoscale composite particles enhance β-cell functions in terms of glucose-stimulated insulin secretion and protect them under stress conditions. Recruiting the β-cells’ “neuron-like” secretory machinery as a target for diabetes treatment use has never been reported before. Such nanoscale composites might therefore provide a unique starting point for designing a novel class of antidiabetic therapeutic agents that possess a unique mechanism of action.