GDNF family receptor complexes are emerging drug targets.
Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), which consist of GDNF, neurturin, artemin and persephin, regulate the development and maintenance of the nervous system. GDNF protects and repairs dopamine-containing neurons, which degenerate in Parkinson's disease, and motoneurons, which die in amyotrophic lateral sclerosis. GDNF and neurturin have shown promise in clinical trials of Parkinson's disease, and artemin is currently undergoing clinical trials for chronic pain treatment. However, the delivery of GFLs into the brain through invasive approaches such as neurosurgery, viral vectors or by the use of encapsulated cells is associated with multiple obstacles. The development of small molecules that specifically activate GFL receptors and that can be applied systemically would overcome most of these problems. The unique nature of the GFL receptors, recent progress in elucidation of the 3D structures of GFLs and GFL-receptor complexes and the use of high-throughput screening have resulted in the development of the first small molecules that mimic the effects of the different GFLs.
Bespalov
Maxim M
MM
Institute of Biotechnology, University of Helsinki, Viikinkaari 9, PO Box 56, FIN-00014 Helsinki, Finland.
Saarma
Mart
M
D000818:Animals; D002908:Chronic Disease; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D018716:Molecular Mimicry; D009414:Nerve Growth Factors / Q000494:pharmacology; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology*
D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors