Designed NGF mimetics with reduced nociceptive signatures in neurons

作者：Thomas Schlichthaerle, Aerin Yang, Damien Detraux, David E. Johnson, Chloe J. Peach, Natasha I. Edman, Catherine Sniezek, Charles A. Williams, Sonali Arora, Neerja Katiyar, Irene Chen, Ali Etemadi, Andrew Favor, David Lee, Connor Kubo, Brian Coventry, Buwei Huang, Stacey Gerben, Nathan M. Ennist, Lukas F. Milles, Banumathi Sankaran, Alex Kang, Hannah Nguyen, Asim K. Bera, Babak Negahdari, Nobuhiko Hamazaki, Devin K. Schweppe, Lance Stewart, Jessica E. Young, Nigel W. Bunnett, Hannele Ruohola‐Baker, Julie Mathieu, Siobhan S. Pattwell, K. Christopher García, David Baker · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.04.14.648806 · 被引用次数：6 · 研究领域：Neuroscience and Neuropharmacology Research、Nerve injury and regeneration、Photochromic and Fluorescence Chemistry

Abstract 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 p75 NTR ; pain sensitization is thought to involve p75 NTR . We sought to overcome this limitation by de novo design of a TrkA agonist that does not bind p75 NTR . 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. Highlights De novo designed TrkA agonists activate MAPK and PI3K-AKT signaling Rigid fusions allow for highly tunable signaling signatures TrkA agonists lead to neurite outgrowth in neuroblastoma cells comparable to retinoic acid Modulation of the TrkA pathway without co-stimulating p75 NTR leads to a downregulation of inflammatory and nociceptive signature in neurons. Graphical Abstract