Designed NGF mimetics with reduced nociceptive signatures in neurons
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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
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De novo designed TrkA agonists activate MAPK and PI3K-AKT signaling
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Rigid fusions allow for highly tunable signaling signatures
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TrkA agonists lead to neurite outgrowth in neuroblastoma cells comparable to retinoic acid
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Modulation of the TrkA pathway without co-stimulating p75 NTR leads to a downregulation of inflammatory and nociceptive signature in neurons.
