Open AccessSmall Molecules Targeting PTPσ–Trk Interactions Promote Sympathetic Nerve Regeneration
Author(s) -
Matthew R. Blake,
Ryan T. Gardner,
Haihong Jin,
Melanie A. Staffenson,
Nicole J. Rueb,
Amy Barrios,
Gregory B. Dudley,
Michael S. Cohen,
Beth A. Habecker
Publication year - 2022
Publication title -
acs chemical neuroscience
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.1c00854
Subject(s) - trk receptor , regeneration (biology) , chondroitin sulfate proteoglycan , neuroscience , tropomyosin receptor kinase b , microbiology and biotechnology , growth cone , axon , tropomyosin receptor kinase a , protein tyrosine phosphatase , neurotrophin , biology , receptor , chemistry , signal transduction , neurotrophic factors , proteoglycan , biochemistry , extracellular matrix
Chondroitin sulfate proteoglycans (CSPGs) prevent sympathetic nerve regeneration in the heart after myocardial infarction and prevent central nerve regrowth after traumatic brain injury and spinal cord injury. Currently, there are no small-molecule therapeutics to promote nerve regeneration through CSPG-containing scars. 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 tropomyosin receptor kinases (Trks), inhibiting their activity and preventing axon outgrowth. Targeting PTPσ-Trk interactions is thus a potential therapeutic target. Here, we describe the development and synthesis of small molecules (HJ-01 and HJ-02) that disrupt PTPσ interactions with Trks, enhance Trk signaling, and promote sympathetic nerve regeneration over CSPGs.
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