Serendipitous Discovery of Short Peptides Dimethylammonium Salt Promoting Neural Differentiation

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The synthesis and in vitro neuronal growth support activity of a novel series of heptapeptides (1-19) are reported here. Structural studies of the peptide 3 (LSAVTFG.DMA) revealed an unexpected dimethylammonium (DMA) salt adduct formation localized at the C-terminal glycine residue. DOSY NMR analysis revealed the presence of two distinct species exhibiting different diffusion coefficients, allowing the differentiation between the peptide and the DMA adduct. Peptide 3 promoted neural differentiation at 100 μM concentration. To identify residues crucial for biological activity, we conducted L- and D-alanine scans with salt and nonsalt form of peptide 3, which resulted in the synthesis of 16 peptide analogs. Findings from the alanine scan revealed that the lead peptides L1A.DMA (13) and S2A.DMA (15) exhibited significant neural progenitor cells or neural stem cells (NPCs/NSCs) differentiation activity. These peptides promote neuronal survival, morphology recovery, increase cell proliferation, and preserve neuronal network integrity under OGD/R and hypoxia/R insult in an in vitro model of ischemic stroke. These results represent the first synthetic approach to new neuromodulatory peptides and deliver important structure-activity relationship (SAR) insights to guide the development of bioactive peptides.