A De Novo Peptide That Induces Axonal Growth Through TrkB Activation.

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), are key regulators of neuronal survival and synaptic plasticity. Impaired BDNF-TrkB signaling is strongly implicated in neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and major depressive disorder. However, the clinical use of BDNF is limited by poor pharmacokinetics and low tissue stability, highlighting the need for alternative TrkB agonists. Many previously reported agonists have shown inconsistent or indirect TrkB activation, raising concerns about their mechanism of action. In this study, we employed the random nonstandard peptides integrated discovery (RaPID) system to identify de novo macrocyclic peptide ligands that bind the extracellular domain of TrkB with high affinity and selectivity. One of the peptides was turned into a dimeric peptide, diTrbL3, which induced TrkB autophosphorylation and activated canonical downstream pathways, including ERK1/2 and AKT, without detectable cross-activation of other receptor tyrosine kinases. Functionally, diTrbL3 promoted axonal elongation and upregulated activity-dependent immediate early genes in primary hippocampal neurons. These findings establish diTrbL3 as a potent de novo TrkB agonist and highlight RaPID-derived macrocyclic peptides as a promising class of BDNF mimetics for targeting TrkB-dependent signaling in neurological disease.