GDNF Mimetics

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:

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