Peptide selected by phage display increases survival of SH‐SY5Y neurons comparable to brain‐derived neurotrophic factor

Brain‐derived neurotrophic factor (BDNF) is a well‐known neuroprotectant and a potent therapeutic candidate for neurodegenerative diseases. However, there are several clinical concerns about its therapeutic applications. In the current study, we designed and developed BDNF‐mimicking small peptides as an alternative to circumvent these problems. A phage‐displayed peptide library was screened using BDNF receptor (neurotrophic tyrosine kinase receptor type2 [NTRK2]) and evaluated by ELISA. The peptide sequences showed similarity to loop2 of BDNF, they were recognized as discontinuous epitopes though. Interestingly, in silico molecular docking showed strong interactions between the peptide three‐dimensional models and the surface residues of the NTRK2 protein at the IgC2 domain. A consensus peptide sequence was then synthesized to generate a mimetic construct (named as RNYK). The affinity binding and function of this construct was confirmed by testing against the native structure of NTRK2 in SH‐SY5Y cells in vitro using flow‐cytometry and MTT assays, respectively. RNYK at 5 ng/mL prevented neuronal degeneration of all‐ trans‐retinoic acid‐treated SH‐SY5Y with equal efficacy to or even better than BDNF at 50 ng/mL. It was selected a desired peptide (named as RNYK) for specific binding to the neurotrophic tyrosine kinase receptor type2 receptor. RNYK conformationally mimicked loop 2 of brain‐derived neurotrophic factor (BDNF). RNYK prevented neuronal degeneration with equal efficacy to or even better than BDNF.