Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration

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Sidorova , Y A & Saarma , M 2020 , ' Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration ' , International Journal of Molecular Sciences , vol. 21 , no. 18 , 6575 . https://doi.org/10.3390/ijms21186575

Title: Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration
Author: Sidorova, Yulia A.; Saarma, Mart
Contributor: University of Helsinki, Divisions of Faculty of Pharmacy
University of Helsinki, Institute of Biotechnology
Date: 2020-09
Language: eng
Number of pages: 20
Belongs to series: International Journal of Molecular Sciences
ISSN: 1422-0067
URI: http://hdl.handle.net/10138/321872
Abstract: Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson's disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer's disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients' selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.
Subject: glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs)
receptor tyrosine kinase Rearranged in Transfection (RET)
RET agonist
GFL mimetic
small molecule
Parkinson's disease
neuropathic pain
neurodegeneration
retinitis pigmentosa
NEURONS-IN-VITRO
GDNF FAMILY
RAT MODEL
ALPHA-SYNUCLEIN
DOUBLE-BLIND
PARKINSON DISEASE
GENE DELIVERY
WEIGHT-LOSS
NEURTURIN
SURVIVAL
1182 Biochemistry, cell and molecular biology
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