A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors.

A proteolytically stable small molecule beta-turn peptidomimetic, termed D3, was identified as an agonist of the TrkA neurotrophin receptor. D3 binds the Ig-like C2 region of the extracellular domain of TrkA, competes the binding of another TrkA agonist, affords selective trophic protection to TrkA-expressing cell lines and neuronal primary cultures, and induces the differentiation of primary neuronal cultures. These results indicate that a small beta-turn peptidomimetic can activate a tyrosine kinase neurotrophin receptor that normally binds a relatively large protein ligand. Agents such as D3 that bind the extracellular domain of Trk receptors will be useful pharmacological agents to address disorders where Trk receptors play a role, by targeting populations selectively.

• Publication year

  2000

• Venue

  Molecular Pharmacology

• Publication date

  2000-02-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0026-895x(24)23211-9PMID 10648649
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.

  1999cited by this paper
• A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat.

  1999cited by this paper
• Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat.

  1999cited by this paper
• Erythropoietin receptor activation by a ligand-induced conformation change.

  1999cited by this paper
• Discovery of a small molecule insulin mimetic with antidiabetic activity in mice.

  1999cited by this paper
• Small molecule and protein-based neurotrophic ligands: agonists and antagonists as therapeutic agents

  1999cited by this paper
• SNAr Cyclizations To Form Cyclic Peptidomimetics of β-Turns

  1998cited by this paper
• Motoneuron Apoptosis Is Blocked by CEP-1347 (KT 7515), a Novel Inhibitor of the JNK Signaling Pathway

  1998cited by this paper
• A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor [see commetns].

  1998cited by this paper
• Developmental Regulation of Apoptosis in Dorsal Root Ganglion Neurons

  1998cited by this paper
• A TrkA-selective, Fast Internalizing Nerve Growth Factor-Antibody Complex Induces Trophic but Not Neuritogenic Signals*

  1998cited by this paper
• Solution Structure and Internal Motion of a Bioactive Peptide Derived from Nerve Growth Factor*

  1998cited by this paper
• Axotomized septal cholinergic neurons rescued by nerve growth factor or neurotrophin-4/5 fail to express the inducible transcription factor c-Jun.

  1997cited by this paper
• Neurotrophins live or let die: does p75NTR decide?

  1997cited by this paper
• Neurotrophins and their receptors in nerve injury and repair.

  1997cited by this paper
• Optimal Nerve Growth Factor Trophic Signals Mediated by Synergy of TrkA and p75 Receptor-Specific Ligands

  1997influential reference
• Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models.

  1997cited by this paper
• Effects of the neurotrophins nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor (BDNF) on neurite growth from adult sensory neurons in compartmented cultures.

  1997cited by this paper
• Nerve Growth Factor (NGF)-Mediated Protection of Neural Crest Cells from Antimitotic Agent-Induced Apoptosis: The Role of the Low-Affinity NGF Receptor

  1996cited by this paper
• Potent human p140-TrkA agonists derived from an anti-receptor monoclonal antibody

  1996influential reference
• Engineering epidermal growth factor for enhanced mitogenic potency

  1996cited by this paper
• Hormone Mimicry

  1996cited by this paper
• Therapeutic potential of the neurotrophins and neurotrophin-CNTF combinations in peripheral neuropathies and motor neuron diseases.

  1996cited by this paper
• Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin

  1996cited by this paper
• Small molecule nerve growth factor analogs image receptors in vivo

  1996cited by this paper
• Inverse agonism: pharmacological curiosity or potential therapeutic strategy?

  1995cited by this paper
• NGF binding to the trk tyrosine kinase receptor requires the extracellular immunoglobulin-like domains.

  1995cited by this paper
• Small Peptide Mimics of Nerve Growth Factor Bind TrkA Receptors and Affect Biological Responses (*)

  1995cited by this paper
• Nerve Growth Factor Binding Site on TrkA Mapped to a Single 24-Amino Acid Leucine-rich Motif (*)

  1995cited by this paper
• Neurotrophin signal transduction by the Trk receptor.

  1994cited by this paper
• The Trk family of neurotrophin receptors.

  1994cited by this paper
• Neurotrophic factors enter the clinic.

  1994influential reference
• Lay-offs follow suspension of clinical trials of protein

  1994cited by this paper
• Loops and Secondary Structure Mimetics: Development and Applications in Basic Science and Rational Drug Design

  1992cited by this paper
• Design and synthesis of a mimetic from an antibody complementarity-determining region.

  1991influential reference
• Nerve growth factor increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons.

  1985cited by this paper
• A rapid radiochemical method for the determination of choline acetyltransferase

  1975cited by this paper

• Selective Modulation of Trk Receptors by Cyclo-Organopeptides

  2025cites this paper
• Selective, Intrinsically Fluorescent Trk Modulating Probes

  2024cites this paper
• Neurotrophin peptidomimetics for the treatment of neurodegenerative diseases.

  2024cites this paper
• A fluorescent electrophile for CLIPS: self indicating TrkB binders.

  2023cites this paper
• Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

  2023cites this paper
• Growth factors and their peptide mimetics for treatment of traumatic brain injury.

  2023influential citation
• Snake venom nerve growth factor-inspired designing of novel peptide therapeutics for the prevention of paraquat-induced apoptosis, neurodegeneration, and alteration of metabolic pathway genes in the rat pheochromocytoma PC-12 cell.

  2023cites this paper
• A, B, C’s of Trk Receptors and Their Ligands in Ocular Repair

  2022cites this paper
• Neurogenic inflammation as a novel treatment target for chronic pain syndromes.

  2022cites this paper
• High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair

  2022cites this paper
• Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction

  2021cites this paper
• Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies

  2021cites this paper
• Current Status of Drug Targets and Emerging Therapeutic Strategies in the Management of Alzheimer's Disease

  2020cites this paper
• Low‐molecular mimetics of nerve growth factor and brain‐derived neurotrophic factor: Design and pharmacological properties

  2020cites this paper
• Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

  2020cites this paper
• Small-Molecule Ligands that Bind the RET Receptor Activate Neuroprotective Signals Independent of but Modulated by Coreceptor GFRα1

  2020cites this paper
• Balancing neurotrophin pathway and sortilin function: Its role in human disease.

  2020cites this paper
• hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay

  2020cites this paper
• Pharmacological interrogation of TrkA-mediated mechanisms in hippocampal-dependent memory consolidation

  2019cites this paper
• Neuroprotection: Pro-survival and Anti-neurotoxic Mechanisms as Therapeutic Strategies in Neurodegeneration

  2019cites this paper
• Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF

  2019cites this paper
• Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development

  2019cites this paper
• Synthesis and In Vitro Neuroprotective Activity of Analogs with Various Spacer Lengths of a Dimeric Dipeptide Mimetic (GK-2) of Nerve Growth Factor

  2019cites this paper
• Synthesis and In Vitro Neuroprotector Activity of Diastereoisomers of a Dimeric Dipeptide Mimetic of Nerve Growth Factor GK-2

  2018cites this paper
• A synthetic snake‐venom‐based tripeptide (Glu‐Val‐Trp) protects PC12 cells from MPP+ toxicity by activating the NGF‐signaling pathway

  2018cites this paper
• Neurotrophin Receptor Signaling as a Therapeutic Target for Huntington's Disease.

  2017cites this paper
• Therapeutic inhibitors for the treatment of dry eye syndrome

  2017cites this paper
• Role of nerve growth factor in plasticity of forebrain cholinergic neurons

  2017cites this paper
• Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm.

  2017cites this paper
• Current and emerging therapy of dry eye disease. Part A: pharmacological modalities

  2017cites this paper
• Expression and signaling of NGF in the healthy and injured retina.

  2017cites this paper
• Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington’s Disease

  2017cites this paper
• Glial cell line-derived neurotrophic factor family ligands and their therapeutic potential

  2016cites this paper
• A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth.

  2016cites this paper
• The Emerging Therapeutic Role of NGF in Alzheimer’s Disease

  2016cites this paper
• Neuroprotective Strategies for Alzheimer’s Disease Prevention and Therapy

  2016cites this paper
• A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

  2015cites this paper
• Behavioral effect of dipeptide NGF mimetic GK-2 in an in vivo model of rat traumatic brain injury and its neuroprotective and regenerative properties in vitro

  2015cites this paper
• A small linear peptide encompassing the NGF N-terminus partly mimics the biological activities of the entire neurotrophin in PC12 cells.

  2015cites this paper
• A proNGF and NGF binding protein, α2Macroglobulin, differentially regulates p75 1 and TrkA receptors and is relevant to neurodegeneration ex vivo and in vivo . 2

  2015cites this paper
• Implication de réseaux de récepteurs membranaires dans la signalisation du NGF et de son précurseur dans les cellules cancéreuses de sein

  2014cites this paper
• New Chemical Entities Entering Phase III Trials in 2013

  2014cites this paper
• Chapter Five - Stimulating Neurotrophin Receptors in the Treatment of Neurodegenerative Disorders

  2014cites this paper
• Combinatorial Assembly of Small Molecules into Bivalent Antagonists of TrkC or TrkA Receptors

  2014cites this paper
• Nerve growth factor novel dipeptide mimetic GK-2 selectively activates TrkA postreceptor signaling pathways and does not cause adverse effects of native neurotrophin

  2014cites this paper
• Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye

  2013influential citation
• Chapter 224 – Neurotrophins

  2013cites this paper
• Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease

  2013cites this paper
• Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

  2013cites this paper
• BB14, a Nerve Growth Factor (NGF)-like peptide shown to be effective in reducing reactive astrogliosis and restoring synaptic homeostasis in a rat model of peripheral nerve injury.

  2012cites this paper
• In silico biological activity of steroids from the marine sponge Axinella carteri

  2012cites this paper
• New Small Molecule Drug Discovery for Alzheimer's Disease

  2012cites this paper
• Ligand-dependent TrkA activity in brain impacts differently on spatial learning and long-term memory

  2011cites this paper
• NIGROSTRIATAL DOPAMINE-NEURON FUNCTION FROM NEUROTROPHIC-LIKE PEPTIDE TREATMENT AND NEUROTROPHIC FACTOR DEPLETION

  2011cites this paper
• Drug discovery and the human kinome: recent trends.

  2011cites this paper
• Peptide mimetics of neurotrophins and their receptors.

  2011cites this paper
• Ligand-Dependent TrkA Activity in Brain Differentially Affects Spatial Learning and Long-Term Memory

  2011cites this paper
• An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye.

  2011cites this paper
• Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.

  2011cites this paper
• Nerve growth factor receptor TrkA exists as a preformed, yet inactive, dimer in living cells

  2011cites this paper
• STRATEGIES FOR TARGETING LENTIVIRAL VECTORS

  2011influential citation
• NIGROSTRIATAL DOPAMINE-NEURON FUNCTION FROM NEUROTROPHIC-LIKE PEPTIDE TREATMENT AND NEUROTROPHIC FACTOR DEPLETION

  2011cites this paper
• Bivalent diketopiperazine-based tropomysin receptor kinase C (TrkC) antagonists.

  2010cites this paper
• A Combinatorial Approach for Targeted Delivery using Small Molecules and Reversible Masking to Bypass Non-Specific Uptake In Vivo

  2010cites this paper
• An agonistic TrkB mAb causes sustained TrkB activation, delays RGC death, and protects the retinal structure in optic nerve axotomy and in glaucoma.

  2010cites this paper
• A monovalent agonist of TrkA tyrosine kinase receptors can be converted into a bivalent antagonist.

  2010cites this paper
• Inhibition of Protein-Protein Interactions by Peptide Mimics

  2010cites this paper
• Cyclotraxin-B, the First Highly Potent and Selective TrkB Inhibitor, Has Anxiolytic Properties in Mice

  2010cites this paper
• A peptidomimetic of NT-3 acts as a TrkC antagonist.

  2009cites this paper
• A neurotrophic rationale for the therapy of neurodegenerative disorders.

  2009cites this paper
• One-pot high-throughput synthesis of beta-turn cyclic peptidomimetics via "volatilizable" supports.

  2009cites this paper
• Inhibition of p75(NTR) in glia potentiates TrkA-mediated survival of injured retinal ganglion cells.

  2009cites this paper
• Bivalent peptidomimetic ligands of TrkC are biased agonists and selectively induce neuritogenesis or potentiate neurotrophin-3 trophic signals.

  2009cites this paper
• Tandem repeat peptide strategy for the design of neurotrophic factor mimetics.

  2008cites this paper
• α2-Macroglobulin Is a Mediator of Retinal Ganglion Cell Death in Glaucoma*

  2008cites this paper
• The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors.

  2008cites this paper
• A New Nerve Growth Factor-Mimetic Peptide Active on Neuropathic Pain in Rats

  2008cites this paper
• Alzheimer’s therapeutics

  2007cites this paper
• Scaffolds for blocking protein-protein interactions.

  2007cites this paper
• Modulation of protein-protein interactions by stabilizing/mimicking protein secondary structure elements.

  2007cites this paper
• Cholinergic Neurodegeneration in Alzheimer's Disease: Basis for Nerve Growth Factor Therapy

  2007cites this paper
• Neurotrophic rationale in glaucoma: A TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo

  2007influential citation
• GDNF family receptor complexes are emerging drug targets.

  2007cites this paper
• Molecular Simulation Approaches to Proteins Structure and Dynamics and to Ligand Design

  2006cites this paper
• p75 Neurotrophin Receptor-Mediated Signaling Promotes Human Hair Follicle Regression (Catagen).

  2006cites this paper
• Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death

  2006cites this paper
• Molecular simulation of the binding of nerve growth factor peptide mimics to the receptor tyrosine kinase A.

  2006cites this paper
• Cyclic-AMP Response Element-Based Signaling Assays for Characterization of Trk Family Tyrosine Kinases Modulators

  2006cites this paper
• Functional mimetics of neurotrophins and their receptors.

  2006cites this paper
• Pharmacokinetics and biodistribution of a small radioiodine labeled nerve growth factor fragment

  2006cites this paper
• A synthetic peptide modeled on PDNF, Chagas' disease parasite neurotrophic factor, promotes survival and differentiation of neuronal cells through TrkA receptor.

  2005cites this paper
• Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities.

  2005cites this paper
• The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease.

  2005cites this paper
• Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

  2004cites this paper
• ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth

  2004cites this paper
• Reduction of cortical TrkA but not p75NTR protein in early‐stage Alzheimer's disease

  2004cites this paper
• Syntheses and activities of new C10 beta-turn peptidomimetics.

  2004cites this paper
• Ectopic expression of the TrkA receptor in adult dopaminergic mesencephalic neurons promotes retrograde axonal NGF transport and NGF-dependent neuroprotection.

  2003cites this paper
• Syntheses of second generation, 14-membered ring beta-turn mimics.

  2003cites this paper
• Selective formation of homo- and heterobivalent peptidomimetics.

  2003cites this paper