Designed NGF mimetics with reduced nociceptive signatures in neurons

  1. Thomas Schlichthaerle
  2. Aerin Yang
  3. Damien Detraux
  4. David E. Johnson
  5. Chloe J. Peach
  6. Natasha I. Edman
  7. Catherine Sniezek
  8. Charles A. Williams
  9. Sonali Arora
  10. Neerja Katiyar
  11. Irene Chen
  12. Ali Etemadi
  13. Andrew Favor
  14. David Lee
  15. Connor Kubo
  16. Brian Coventry
  17. Buwei Huang
  18. Stacey Gerben
  19. Nathan Ennist
  20. Lukas Milles
  21. Banumathi Sankaran
  22. Alex Kang
  23. Hannah Nguyen
  24. Asim K Bera
  25. Babak Negahdari
  26. Nobuhiko Hamazaki
  27. Devin K. Schweppe
  28. Lance Stewart
  29. Jessica E. Young
  30. Nigel W. Bunnett
  31. Hannele Ruohola-Baker
  32. Julie Mathieu
  33. Siobhan S. Pattwell
  34. K. Christopher Garcia
  35. David Baker
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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 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 p75NTRleads to a downregulation of inflammatory and nociceptive signature in neurons.

Graphical Abstract

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