A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration

Chem Biol. 2009 Jul 31;16(7):691-701. doi: 10.1016/j.chembiol.2009.05.006. Epub 2009 Jul 16.

Abstract

Secreted semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. We screened a peptoid combinatorial library to search for semaphorin 3A inhibitors, and identified a peptoid (SICHI: semaphorin Induced chemorepulsion inhibitor) that blocks semaphorin 3A-chemorepulsion and growth-cone collapse in axons at millimolar concentrations. SICHI inhibits the binding of semaphorin 3A to its receptor complex (neuropilin 1/plexin A1) and semaphorin 3A-induced phosphorylation of GSK3. Chemorepulsion induced by semaphorin 3F or netrin 1 is not blocked by SICHI. We also show that SICHI promotes neural regeneration of damaged axons. We suggest that SICHI, a selective inhibitor of semaphorin 3A, is of therapeutic interest for approaches aimed at promoting axonal regeneration and brain repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology*
  • Glycogen Synthase Kinase 3 / metabolism
  • Growth Cones
  • Mice
  • Nerve Growth Factors
  • Nerve Regeneration
  • Netrin-1
  • Peptide Library
  • Phosphorylation
  • Regeneration*
  • Semaphorin-3A / antagonists & inhibitors*
  • Tumor Suppressor Proteins

Substances

  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Peptide Library
  • Semaphorin-3A
  • Tumor Suppressor Proteins
  • Netrin-1
  • Glycogen Synthase Kinase 3