{"paper_id":"0b74591c-c832-4141-8805-0674e9f39e3f","body_text":"Designed NGF mimetics with reduced nociceptive signatures in neurons\nAbstract\nThe 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.\nHighlights\nDe novo designed TrkA agonists activate MAPK and PI3K-AKT signaling\nRigid fusions allow for highly tunable signaling signatures\nTrkA agonists lead to neurite outgrowth in neuroblastoma cells comparable to retinoic acid\nModulation of the TrkA pathway without co-stimulating p75NTR leads to a downregulation of inflammatory and nociceptive signature in neurons.\nCompeting Interest Statement\nThe authors plan to file a patent application. D.K.S. is a consultant and/or collaborator with ThermoFisher Scientific, AI Proteins, Genentech, and Matchpoint Therapeutics.\n- Biochemistry (17681)\n- Bioengineering (13890)\n- Bioinformatics (41929)\n- Biophysics (21446)\n- Cancer Biology (18586)\n- Cell Biology (25492)\n- Clinical Trials (138)\n- Developmental Biology (13374)\n- Ecology (19897)\n- Epidemiology (2067)\n- Evolutionary Biology (24308)\n- Genetics (15606)\n- Genomics (22497)\n- Immunology (17736)\n- Microbiology (40385)\n- Molecular Biology (17175)\n- Neuroscience (88584)\n- Paleontology (666)\n- Pathology (2831)\n- Pharmacology and Toxicology (4822)\n- Physiology (7641)\n- Plant Biology (15149)\n- Synthetic Biology (4293)\n- Systems Biology (9822)\n- Zoology (2271)","source_license":"CC-BY-4.0","license_restricted":false}