GDNF Mimetics

The major goal of the research in the Saarma lab is to develop neuroprotective and neuroregenerative drugs for disease-modifying treatment of nervous system disorders caused by the death of neuronal cells. In particular, we focus on Parkinson’s disease and neuropathic pain caused by the death of dopamine and sensory neurons, respectively. No cure is available for either of these conditions. Existing treatments alleviate symptoms, but they are unable to stop, prevent, or revert the degeneration of neurons. In addition, available drugs have serious adverse effects and their efficacy vanishes over time. We aim to find a treatment that stops neuronal degeneration, restores the function of remaining neurons and can be delivered to patients in a convenient form. To achieve these goals, we pursue two lines of research: (i) we are developing small molecules acting similarly to neurotrophic factors; and (ii) we evaluate neurorestorative properties of compounds with known positive effects in animal models of Parkinson’s disease. 

Neurotrophic factors are the proteins responsible for the development and maintenance of the nervous system and they are able to protect and regenerate multiple neuronal populations. However, their clinical use is complicated. Using a combination of rational drug design methods and a set of biological assays, we identified chemical compounds specifically targeting the receptors of glial cell line-derived neurotrophic factor (GDNF). We demonstrated that these molecules, GDNF mimetics, were able to support cultured dopamine and sensory neurons, as well as alleviate motor symptoms of Parkinson’s disease and neuropathic pain in animal models. Moreover, they protected sensory neurons from surgery-induced loss. Currently, we are working on optimization of the pharmacological properties of these compounds.

References:

  1. Sidorova YA, Bespalov MM, Wong AW, Kambur O, Jokinen V, Lilius TO, Suleymanova I, Karelson G, Rauhala P V., Karelson M, Osborne PB, Keast JR, Kalso EA, Saarma M (2017) A Novel Small Molecule GDNF Receptor RET Agonist , BT13 , Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat. Front Parmacology 8:1–18. 10.3389/fphar.2017.00365
  2. Ivanova L, Tammiku-Taul J, Sidorova Y, Saarma M, Karelson M (2018) Small-Molecule Ligands as Potential GDNF Family Receptor Agonists. ACS Omega 3:1022–1030. 
  3. Bespalov MM, Sidorova YA, Suleymanova I, Thompson J, Kambur O, Viljami J, Lilius T, Karelson G, Puusepp L, Rauhala P, Kalso E, Karelson M, Saarma M (2016) Novel agonist of GDNF family ligand receptor RET for the treatment of experimental neuropathy. BioRxiv. 10.1101/061820
  4. Saarenpää T, Kogan K, Sidorova Y, Mahato AK, Tascón I, Kaljunen H, Li Y, Kallijärvi J, Jurvansuu J, Saarma M, Goldman A (2017) Zebrafish GDNF and its co-receptor GFRα1 activate the human RET receptor and promote the survival of dopaminergic neurons in vitro. PLoS One:e0176166. 10.1371/journal.pone.0176166
  5. Sidorova YA, Saarma M (2016) Glial cell line-derived neurotrophic factor family ligands and their therapeutic potential. Mol Biol 50:521–531. 10.1134/S0026893316040105