Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

Anna Munder; Yoni Moskovitz; Aviv Meir; Shirin Kahremany; Laura Levy; Michal Kolitz-Domb; Guy Cohen; Efrat Shtriker; Olga Viskind; Jean Paul Lellouche; Hanoch Senderowitz; Steven D. Chessler; Edward E. Korshin; Sharon Ruthstein; Arie Gruzman

doi:10.1039/c8md00419f

Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

Anna Munder, Yoni Moskovitz, Aviv Meir, Shirin Kahremany, Laura Levy, Michal Kolitz-Domb, Guy Cohen, Efrat Shtriker, Olga Viskind, Jean Paul Lellouche, Hanoch Senderowitz, Steven D. Chessler, Edward E. Korshin, Sharon Ruthstein, Arie Gruzman

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Pancreatic β-cell membranes and presynaptic areas of neurons contain analogous protein complexes that control the secretion of bioactive molecules. These complexes include the neuroligins (NLs) and their binding partners, the neurexins (NXs). It has been recently reported that both insulin secretion and the proliferation rates of β-cells increase when cells are co-cultured with full-length NL-2 clusters. The pharmacological use of full-length protein is always problematic due to its unfavorable pharmacokinetic properties. Thus, NL-2-derived short peptide was conjugated to the surface of polyamidoamine-based (PAMAM) dendrimers. This nanoscale composite improved β-cell functions in terms of the rate of proliferation, glucose-stimulated insulin secretion (GSIS), and functional maturation. This functionalized dendrimer also protected β-cells under cellular stress conditions. In addition, various novel peptidomimetic scaffolds of NL-2-derived peptide were designed, synthesized, and conjugated to the surface of PAMAM in order to increase the biostability of the conjugates. However, after being covered by peptidomimetics, PAMAM dendrimers were inactive. Thus, the original peptide-based PAMAM dendrimer is a leading compound for continued research that might provide a unique starting point for designing an innovative class of antidiabetic therapeutics that possess a unique mode of action.

Original language	English
Pages (from-to)	280-293
Number of pages	14
Journal	MedChemComm
Volume	10
Issue number	2
DOIs	https://doi.org/10.1039/c8md00419f
State	Published - 1 Feb 2019

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry.

Funding

This study was supported by a Bar-Ilan University new faculty grant, a D-cure (Diabetes Care in Israel) Young Investigator Award, and a NOFAR program (Israel Ministry of Industry) for A. G. The Israel Science Foundation (application number 117/2014) provided a grant for A. G. and J.-P. L. In addition, S. K. is thankful for the support of her work by the Wolf Foundation. S. D. C. was supported by NIH/NIDDK grant R01DK080971. G. C. is partially supported by the Israel Ministry of Science and Technology. This work was also funded by the 7th Framework RTD European Project (FP7-530 NMP-2010-LARGE-4 area) – Large Collaborative Projects – Project 531 SaveMe (grant agreement no. 263307) for J.-P. L. and finally, by The Bar-University Rector's Grant for Interdisciplinary Research (2017) for A. G., J.-P. L. and H. S. We would like to thank Steve Manch for the English editing of the manuscript.

Funders	Funder number
7th Framework RTD European Project	531 SaveMe, 263307, FP7-530 NMP-2010-LARGE-4
Israel Ministry of Industry
NIH/NIDDK	R01DK080971
Wolf Foundation
Bar-Ilan University
Israel Science Foundation	117/2014
Ministry of science and technology, Israel

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Munder, A., Moskovitz, Y., Meir, A., Kahremany, S., Levy, L., Kolitz-Domb, M., Cohen, G., Shtriker, E., Viskind, O., Lellouche, J. P., Senderowitz, H., Chessler, S. D., Korshin, E. E., Ruthstein, S., & Gruzman, A. (2019). Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions. MedChemComm, 10(2), 280-293. https://doi.org/10.1039/c8md00419f

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title = "Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions",

abstract = "Pancreatic β-cell membranes and presynaptic areas of neurons contain analogous protein complexes that control the secretion of bioactive molecules. These complexes include the neuroligins (NLs) and their binding partners, the neurexins (NXs). It has been recently reported that both insulin secretion and the proliferation rates of β-cells increase when cells are co-cultured with full-length NL-2 clusters. The pharmacological use of full-length protein is always problematic due to its unfavorable pharmacokinetic properties. Thus, NL-2-derived short peptide was conjugated to the surface of polyamidoamine-based (PAMAM) dendrimers. This nanoscale composite improved β-cell functions in terms of the rate of proliferation, glucose-stimulated insulin secretion (GSIS), and functional maturation. This functionalized dendrimer also protected β-cells under cellular stress conditions. In addition, various novel peptidomimetic scaffolds of NL-2-derived peptide were designed, synthesized, and conjugated to the surface of PAMAM in order to increase the biostability of the conjugates. However, after being covered by peptidomimetics, PAMAM dendrimers were inactive. Thus, the original peptide-based PAMAM dendrimer is a leading compound for continued research that might provide a unique starting point for designing an innovative class of antidiabetic therapeutics that possess a unique mode of action.",

author = "Anna Munder and Yoni Moskovitz and Aviv Meir and Shirin Kahremany and Laura Levy and Michal Kolitz-Domb and Guy Cohen and Efrat Shtriker and Olga Viskind and Lellouche, {Jean Paul} and Hanoch Senderowitz and Chessler, {Steven D.} and Korshin, {Edward E.} and Sharon Ruthstein and Arie Gruzman",

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Munder, A, Moskovitz, Y, Meir, A, Kahremany, S, Levy, L, Kolitz-Domb, M, Cohen, G, Shtriker, E, Viskind, O, Lellouche, JP , Senderowitz, H, Chessler, SD, Korshin, EE , Ruthstein, S & Gruzman, A 2019, 'Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions', MedChemComm, vol. 10, no. 2, pp. 280-293. https://doi.org/10.1039/c8md00419f

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AU - Munder, Anna

AU - Moskovitz, Yoni

AU - Meir, Aviv

AU - Kahremany, Shirin

AU - Levy, Laura

AU - Kolitz-Domb, Michal

AU - Cohen, Guy

AU - Shtriker, Efrat

AU - Viskind, Olga

AU - Lellouche, Jean Paul

AU - Senderowitz, Hanoch

AU - Chessler, Steven D.

AU - Korshin, Edward E.

AU - Ruthstein, Sharon

AU - Gruzman, Arie

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AB - Pancreatic β-cell membranes and presynaptic areas of neurons contain analogous protein complexes that control the secretion of bioactive molecules. These complexes include the neuroligins (NLs) and their binding partners, the neurexins (NXs). It has been recently reported that both insulin secretion and the proliferation rates of β-cells increase when cells are co-cultured with full-length NL-2 clusters. The pharmacological use of full-length protein is always problematic due to its unfavorable pharmacokinetic properties. Thus, NL-2-derived short peptide was conjugated to the surface of polyamidoamine-based (PAMAM) dendrimers. This nanoscale composite improved β-cell functions in terms of the rate of proliferation, glucose-stimulated insulin secretion (GSIS), and functional maturation. This functionalized dendrimer also protected β-cells under cellular stress conditions. In addition, various novel peptidomimetic scaffolds of NL-2-derived peptide were designed, synthesized, and conjugated to the surface of PAMAM in order to increase the biostability of the conjugates. However, after being covered by peptidomimetics, PAMAM dendrimers were inactive. Thus, the original peptide-based PAMAM dendrimer is a leading compound for continued research that might provide a unique starting point for designing an innovative class of antidiabetic therapeutics that possess a unique mode of action.

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Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

Abstract

Bibliographical note

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