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Cited by 58Nerve injury and regenerationChemical Synthesis and AnalysisComputational Drug Discovery Methods

The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.

Bivalent Peptidomimetic Ligands of TrkC Are Biased Agonists and Selectively Induce Neuritogenesis or Potentiate Neurotrophin-3 Trophic Signals

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Chen, Dianjun, Brahimi, Fouad, Angell, Yu, Li, Yu-Chin, Moscowicz, Jennifer, Saragovi, H. Uri, Burgess, Kevin·2009·ACS Chemical Biology
DOI 10.1021/cb9001415PMC PMC2756187
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Abstract

This study was initiated to find small molecule ligands that would induce a functional response when docked with neurotrophin Trk receptors. "Minimalist" mimics of beta-turns were designed for this purpose. These mimics are (i) rigid, yet easily folded into turn-like conformations, and (ii) readily accessible from amino acids bearing most of the natural side chains. Gram quantities of 16 of these turn mimics were prepared and then assembled into 152 fluorescein-labeled bivalent peptidomimetics via a solution-phase combinatorial method. Fluorescence-based screening of these molecules using cells transfected with the Trk receptors identified 10 potential ligands of TrkC, the receptor for neurotrophin-3. Analogues of these bivalent peptidomimetics with biotin replacing the fluorescein label were then prepared and tested to confirm that binding was not due to the fluorescein. Several assays were conducted to find the mode of action of these biotinylated compounds. Thus, direct binding, survival and neuritogenic, and biochemical signal transduction assays showed 8 of the original 10 hits were agonistic ligands binding to the ectodomain of TrkC. Remarkably, some peptidomimetics afford discrete signals leading to either cell survival or neuritogenic differentiation. The significance of this work is three-fold. First, we succeeded in finding small, selective, proteolytically stable ligands for the TrkC receptor; there are very few of these in the literature. Second, we show that it is possible to activate distinct and biased signaling pathways with ligands binding at the ectodomain of wild-type receptors. Third, the discovery that some peptidomimetics initiate different modes of cell signaling increases their potential as pharmacological probes and therapeutic leads.

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Crossref · 10.1021/cb9001415

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  • BMS355349 is a selective potentiator of NT-3 mediated TrkA and TrkB receptor activity and induces neurogenesis.

    “BMS355349 has been described as a selective potentiator of NT-3 mediated TrkA and TrkB receptor activity and has proven to induce neurogenesis (Chen et al. 2009; Lewis et al. 2006).”

    From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Chen et al. 2009

    The Results and Discussion sections describe TrkC-targeting peptidomimetics that induce neuritogenic differentiation, but do not identify them as BMS355349. Searches for BMS355349 and BMS 355349 found no passage establishing its effects on NT-3-mediated TrkA or TrkB activity or neurogenesis. The paper’s findings about other compounds cannot verify the claim about BMS355349. (LLM, conf=0.76)

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Research works printed but not linked: 4

  1. Zaccaro M. C., 2005, Chem. Biol., 12, 1015, 10.1016/j.chembiol.2005.06.015 · DOI
  2. Reyes S. J., 2006, Chem. Soc. Rev., 35, 416
  3. Wilkie N., 2001, J. Neurol., 78, 1135
  4. Ivanisevic L., 2003, Oncogene, 22, 5677, 10.1038/sj.onc.1206864 · DOI

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Metadata

Authors
Chen, D., Brahimi, F., Angell, Y., Li, Y.-C., Moscowicz, J., Saragovi, H. U., & Burgess, K.
Affiliations
  • Texas A&M University (US)
  • Jewish General Hospital (CA)
Corresponding author
  • Saragovi, H. Uri
  • Burgess, Kevin
ORCID
Venue
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Published
2009-09-08
Volume
4
Issue
9
Pages
769-781
ISSN
  • 1554-8929 (ISSN-L)
  • 1554-8937
DOI
10.1021/cb9001415
PMC
PMC2756187
OpenAlex
W2051793716
Cited by
56
References
56
Citations by year
2026: 2 · 2025: 7 · 2024: 3 · 2023: 1 · 2022: 3 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 1 · 2016: 5 · 2015: 1 · 2014: 4 · 2013: 5 · 2012: 4
FWCI
1.52
Type
journal article
Language
en
Open access
Locations
  • ACS Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (MH070040, R01MH070040)
  • National Institute of General Medical Sciences (P41GM076261, GM 076261)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
TrkC receptor, neurotrophin-3, biased agonists, neurite outgrowth, cell survival signaling, receptor ectodomain, β-turn mimics, small-molecule ligands, fluorescence-based screening
MeSH terms
Animals, Cell Survival, Ligands, Protein Binding, Transfection, Signal Transduction, Receptor, trkC, Neurotrophin 3, Biomimetics, NIH 3T3 Cells, Mice, Small Molecule Libraries, Neurogenesis

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