Designed NGF mimetics with reduced nociceptive signatures in neurons

2025 · doi:10.1101/2025.04.14.648806
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The paper de novo designs homodimeric TrkA agonist constructs intended to stimulate nerve growth factor (NGF) signaling while avoiding p75NTR binding, which is implicated in pain sensitization. Using engineered TrkA-binding geometries, the authors identify designs that elicit strong TrkA-mediated MAPK and PI3K-AKT signaling and then test them in transdifferentiated neurons and neuroblastoma cell lines, where they drive neurite outgrowth and neuronal differentiation. A key finding is that these TrkA agonists produce “considerably reduced” transcription of inflammation and pain-related genes compared with conditions associated with nociceptive signatures, with the stated caveat that the work is based on cellular models rather than clinical pain outcomes. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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
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Designed NGF mimetics with reduced nociceptive signatures in neurons 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 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. 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 p75NTR leads to a downregulation of inflammatory and nociceptive signature in neurons. Competing Interest Statement The 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. - Biochemistry (17681) - Bioengineering (13890) - Bioinformatics (41929) - Biophysics (21446) - Cancer Biology (18586) - Cell Biology (25492) - Clinical Trials (138) - Developmental Biology (13374) - Ecology (19897) - Epidemiology (2067) - Evolutionary Biology (24308) - Genetics (15606) - Genomics (22497) - Immunology (17736) - Microbiology (40385) - Molecular Biology (17175) - Neuroscience (88584) - Paleontology (666) - Pathology (2831) - Pharmacology and Toxicology (4822) - Physiology (7641) - Plant Biology (15149) - Synthetic Biology (4293) - Systems Biology (9822) - Zoology (2271)

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