Schlichthaerle, T.; Yang, A.; Detraux, D.; Johnson, D. E.; Peach, C. J.; Edman, N. I.; Sniezek, C.; Williams, C. A.; Arora, S.; Katiyar, N.; Chen, I.; Etemadi, A.; Favor, A.; Lee, D.; Kubo, C.; Coventry, B.; Huang, B.; Gerben, S.; Ennist, N. M.; Milles, L.; Sankaran, B.; Kang, A.; Nguyen, H.; Bera, A. K.; Negahdari, B.; Hamazaki, N.; Schweppe, D. K.; Stewart, L.; Young, J. E.; Bunnett, N. W.; Ruohola-Baker, H.; Mathieu, J.; Pattwell, S.; Garcia, K. C.; Baker, D.

The clinical use of Nerve Growth Factor (NGF) for neuronal regeneration has been hampered by pain sensitization side effects. NGF signals through the receptor tyrosine kinase TrkA and the co-receptor p75NTR; pain sensitization is thought to involve p75NTR. We sought to overcome this limitation by de novo design of a TrkA agonist that does not bind p75NTR. We designed homodimeric TrkA engaging constructs that dimerize TrkA subunits in a variety of geometries, and identified those eliciting the strongest signaling. The resulting designed agonists are able to stimulate transdifferentiated neurons and neuroblastoma cell lines, leading to neurite outgrowth and neuronal differentiation, with considerably reduced transcription of inflammation and pain related genes. These agonists are promising candidates for promoting neuronal regeneration without adverse side effects.