GDNF Mimetics

The major goal of the research of Dr. Sidorova’s team 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 which appear as a result of the death of dopamine and sensory neurons, respectively. No cure is currently 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 restore multiple neuronal populations. However, their clinical use is complicated. In patients with Parkinson’s disease neurotrophic factor have to be surgically delivered directly into the brain as they are unable to cross through the blood brain barrier. Using a combination of rational drug design methods and a set of biological assays, we identified three scaffolds of 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 neurons expressing GDNF receptors. Moreover in animal models of Parkinson’s disease and neuropathic pain these compounds alleviated motor symptoms and showed analgesic properties. GDNF mimetics also protected sensory neurons from surgery-induced loss. These compounds cross through the blood brain barrier and therefore can be formulated as pills that are taken orally. Currently, we are optimizing efficacy and pharmacological properties of discovered GDNF mimetics aiming to progress them into clinical trials in the next few years.

Our team demonstrated that the compounds structurally related to diols show neuroprotective properties in cultured dopamine neurons and in animal model of Parkinson’s disease. In collaboration with colleagues from Vorozhtsov Institute of Organic Chemistry, Novosibirsk, Russian Academy of Science, we generated a series of diol analogues. Currently we are testing these derivatives in cultured dopamine neurons to identify the ones with improved efficacy. Diols are currently entering clinical trials in patients with Parkinson’s disease as symptomatic treatment. Further development of their neuroprotective properties can provide a disease-modifying solution and significantly advance the management of this devastating disorder.

References:

  1. Renko JM, Voutilainen MH, Visnapuu T, Sidorova YA, Saarma M, Tuominen RK (2020). GDNF receptor agonist alleviates motor imbalance in unilateral 6-hydroxydopamine model of Parkinson’s disease. Frontiers in Neurology and Neuroscience Research, in press.
  2. Viisanen-Kuopila H, Nuotio U, Kambur O, Mahato, AK, Jokinen V, Lilius T, Li W, Hélder A. Santos HA, Rauhala P, Kalso E, Karelson M, Sidorova YA (2020). Novel RET agonist for the treatment of experimental neuropathies. Mol. Pain. 16. 10.1177/1744806920950866
  3. Jmaeff S, Sidorova Y, Lippiatt H, Barcelona PF, Nedev H, Saragovi LM, Hancock MA, Saarma M, Saragovi HU. (2020). Small-molecule ligands that bind the RET receptor activate neuroprotective signals independent of but modulated by co-receptor GFRα1. Mol Pharmacol. 2020 May 3. 10.1124/mol.119.118950.
  4. Jmaeff S, Sidorova YA, Nedev H, Saarma M, Saragovi HU. (2020). Small molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors. J.Biol. Chem. 295(19):6532-6542. 10.1074/jbc.RA119.011802
  5. Mahato AK, Kopra J, Renko JM, Korhonen I, Pulkkinen N, Visnapuu T, Domanskyi A, Bespalov MM, Ronken E, Piepponen TP, Voutilainen MH, Tuominen RK, Karelson M, Sidorova YA, Saarma M. (2020). Glial cell line-derived neurotrophic factor receptor rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release in vivo. Mov Disord. 35(2), p. 245-255. 10.1002/mds.27943
  6. Sidorova YA, Saarma M (2020). Can growth factors cure Parkinson’s disease? Trends Pharmacol Sci. 41(12) P. 909-922. 10.1016/j.tips.2020.09.010.
  7. Mahato AK, Sidorova YA (2020). RET receptor tyrosine kinase: role in neurodegeneration, obesity and cancer. IJMS special issue “Tyrosine kinases in health and disease”. IJMS. 21 (19) 7108 10.3390/ijms21197108
  8. Sidorova YA, Saarma M. (2020). Small molecules and peptides targeting glial cell line-derived neurotrophic factor receptors for the treatment of neurodegeneration. IJMS. 21 (8) 6575.
  9. Mahato AK, Sidorova YA (2020). Glial cell line-derived neurotrophic factors (GFLs) and small molecules targeting RET receptor for the treatment of pain and Parkinson’s disease. Cell and Tissue Research. 10.1007/s00441-020-03227-4
  10. Ardashov OV, Pavlova AV, Mahato AK, Sidorova YA, Morozova EA, Korchagina DV, Salnikov GE, Genaev AM, Patrusheva OS, LI-Zhulanov NS, Tolstikova TG, Volcho KP, Slakhutdinov NF. (2019). A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson’s Disease. ACS Chem. Neurosci. 10(10), p. 4337-4349.
  11. Sidorova YA, Volcho KP, Salahutdinov NF. (2019). Neuroregeneration in Parkinson's Disease: From Proteins to Small Molecules. Curr Neuropharmacol. 17(3):268-287.
  12. Ivanova L, Tammiku-Taul J, García-Sosa AT, Sidorova Y, Saarma M, Karelson M. (2018). Molecular Dynamics Simulations of the Interactions between Glial Cell Line-Derived Neurotrophic Factor Family Receptor GFRα1 and Small-Molecule Ligands. ACS Omega. 30;3(9):11407-11414.
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. Sidorova YA, Mätlik K, Paveliev M, Lindahl M, Piranen E, Milbrandt J, Arumäe U, Saarma M, Bespalov MM. (2010). Persephin signaling through GFRalpha1: The potential for the treatment of Parkinson's disease. Mol. Cell. Neurosci. 44(3) P. 223-232.
  19. Piltonen M, Bespalov MM, Ervasti D, Matilainen T, Sidorova YA, Rauvala H, Saarma M, Männistö PT. (2009). Heparin binding determinants of GDNF reduce its tissue distribution but are beneficial for the protection of nigral dopaminergic neurons. Exp. Neurol. 219(2) P. 499-506.
  20. Parkash V, Leppänen V-M, Virtanen H, Jurvansuu JM, Bespalov MM, Sidorova YA, Runeberg-Roos P, Saarma M, Goldman A. (2008). The Structure of the GDNF2-GFRα12 Complex: Insights into RET Signalling and Heparin Binding. J. Biol. Chem. 283(50) P. 35164-35172.