129
Small Molecules Promoting Nerve Regeneration
Oregon Health and Science University
Small molecule
Neurology
Hit To Lead or Lead Optimization
• CSPGs bind to monomers of receptor protein tyrosine phosphatase sigma (PTPσ) on the surface of neurons, enhancing the ability of PTPσ to bind and dephosphorylate Trk tyrosine kinases, inhibiting their activity and preventing axon outgrowth.
• Protein tyrosine phosphatase receptor sigma (PTPσ), expressed on sympathetic nerves, is a major receptor for CSPG; therefore, novel compounds were designed to disrupt the PTPσ signaling pathway and tested for restoring axon growth in the presence of CSPG.
• The novel compounds increased axon outgrowth over culture plates containing CSPG in a dose dependent manner, with full restoration achieved at concentrations in the range of 100 nM. In vivo testing 3 days following myocardial infarction in mice found that these compounds restored normal nerve density within the infarct, without signs of toxicity or widespread non-specific binding.
• These compounds were capable of reducing isoproterenol-induced arrhythmias post-infarction and also restored cardiac output to levels observed in sham uninjured mice.
• These compounds have demonstrated efficacy in vitro and in vivo to promote nerve regeneration through injury and CSPG expression and could improve outcomes for a wide range of injuries that cause permanent nerve damage.
WO2022051233A1
• Therapeutics That Promote Sympathetic Reinnervation Modulate the Inflammatory Response After Myocardial Infarction. JACC Basic Transl Sci. (2022)
• Small Molecules Targeting PTPσ-Trk Interactions Promote Sympathetic Nerve Regeneration. ACS Chem Neurosci. (2022)
