Development of Novel Reagents for Generating Islets β-Cells and Enhancing their Function Based on Clustered Nanoformulation of Neuroligin-2 Mimetics

Β-cell membrane and presynaptic zones of neurons have sites of similar protein complexes mediating secretion of bioactive molecules. Synaptic proteins that mediate interactions between neurons and guide the formation and functional maturation of synapses have been recently identified. These synapse-inducing proteins include neuroligins and their binding partners: neurexins. It was found that insulin secretion and the proliferation rate of β-cells increased when β-cells were co-cultured with cells overexpressing neuroligins. We propose that neuroligin-derived molecules arranged in clusters can enhance β-cell functions by increasing insulin secretion, functional maturity and protecting in stress conditions. Several peptides were derived from crystal structures of different neuroligins and neurexins using molecular modeling method. Based on these results, we designed and fabricated poly(amidoamine) dendrimer decorated by the peptide. The compound increased insulin secretion, induced the formation of islets-like cellular structures, proliferation rate and protected β-cell line against oxidative and ER stresses. Identical effect on the insulin secretion was also obtained in isolated mice islets. Moreover, diabetic mice treated by our compound significantly reduced blood glucose level in comparison to untreated mice.

In summary, we report about the development of a new class of potential antidiabetic compounds. Such systems might support β-cell differentiation and viability in vitro, which will increase survival of further β-cell transplants in vivo. Such approach of using the neuron secretion machinery presented in β-cells as a target for antidiabetic drug design was never reported before.