Small Molecules Targeting PTPσ–Trk Interactions Promote Sympathetic Nerve Regeneration
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...
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Published in | ACS chemical neuroscience Vol. 13; no. 5; pp. 688 - 699 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
02.03.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors contributed equally Author Contributions: MRB, RTG, BAH designed and conducted experiments, collected and analyzed data, and wrote the manuscript. MSC developed the small molecules, designed and conducted experiments and wrote the manuscript. HJ helped design and synthesize the small molecules. MS conducted experiments and analyzed data. NJR, AMB, GBD designed, conducted, analyzed phosphatase screening experiments, produced Illudalic acid and provided input on the manuscript. Current address: Ryan T. Gardner, Merz Therapeutics, 6601 Six Forks Road, suite 430, Raleigh, NC, 27615 Current address: Haihong Jin, Atomwise, 717 Market St #800, San Francisco, CA 94103 |
ISSN: | 1948-7193 1948-7193 |
DOI: | 10.1021/acschemneuro.1c00854 |