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A European training network for the discovery of neurotrophins small molecule mimetics as candidate therapeutic agents for neurodegeneration and neuroinflammation

Periodic Reporting for period 1 - EuroNeurotrophin (A European training network for the discovery of neurotrophins small molecule mimetics as candidate therapeutic agents for neurodegeneration and neuroinflammation)

Reporting period: 2018-01-01 to 2019-12-31

Neurodegenerative diseases (ND) like Alzheimer’s Disease (AD), Parkinson’s Disease (PD) Multiple Sclerosis (MS) and Neurone Disease (MND) are on the rise in developed societies worldwide. Just AD affects 36 million people worldwide and 7 million in Europe. The economic burden for ND exceeds 724 billion € and it will become a trillion euros by 2020. Currently, there exists no cure for any ND, and most of the available drugs fail to tackle ND pathogenesis.
Neurotrophins are a family of closely related secreted proteins that have been shown to control a number of aspects of survival, development and function of neurons both in the central and the peripheral nervous systems. Preclinical studies point to the therapeutic potential of neurotrophins in preventing or slowing the progression of ND. Thus, neurotrophins have been proposed as therapeutic agents for neurodegenerative diseases. However, the poor pharmacokinetic properties of neurotrophins, render their use as drugs prohibitive.
A potential approach for addressing neurotrophin limitations is the development of synthetic, small molecule, neurotrophin mimetics with favourable profiles of stability, tissue penetration and targeted biological actions.
EuroNeurotrophin is the first European consortium to study small molecule neurotrophin mimetics (synthetic or natural) in depth, use them as molecular probes to interrogate neurotrophins, and emphasise their clinical translation.
The consortium builds on previous successful collaborations, enriched with key specialists and partners. The consortium consists of 12 leading European research groups and 6 private companies of complementary expertise covering all steps of drug discovery and development. Jointly, it aims to accelerate the translation of identified lead compounds to drug candidate molecules through the collaborative training of 14 early-stage researchers.
The EuroNeurotrophin objectives are to:
1. Develop small molecule mimetics of neurotrophins capitalising on a synergistic combination of medicinal chemistry, isolation of natural products, computer-aided drug design, structural biology, molecular biology, pharmacology high throughput screening (HTS) and ‘omics’ technologies.
2.. Educate 14 young researchers regarding the knowledge underpinning the neurotrophin related field and on drug and natural products research for neurodegenerative diseases.
3. Provide to 14 ESRs a multidisciplinary research and industrial training, as well as training in a comprehensive set of transferable skills.
4. Create a new generation of young scientists with a broad understanding and skill set in chemical biology with emphasis on the neuroscience field.
During the 24 months of the EuroNeurotrophin a multidisciplinary training program was available to the ESRs. Local training courses and workshops were selected based on the needs and interests of the fellows. The network-wide schools and courses educated the ESRs on cutting edge issues of chemistry and biology on drug discovery and development for neurodegenerative diseases and in highly desirable transferable skills. In the context of the 1st EuroNeurotrophin Training Week the ESRs attended a 2-day workshop on drug discovery and development for neurodegenerative diseases held by by Novartis Hellas SACI in which they learned all the steps required to bring a new drug to the market. They also attended a 4-day School on Computer-Assisted Drug Design, Synthesis and Isolation from Natural Sources of Small Molecule Neurotrophin Mimetics. During the 2nd Training Week the ESRs attended a 4-day long school which included theoretical lectures on in vivo models of neurodegenerative disorders (AD, MD and MND), as well as hands-on experience in analysis of these models including ethics of animal experimentation. In addition, the ESRs attended a two-day workshop on Patenting and Commercialising Novel Biomedical Inventions held by Ventac Partners. The course included all the steps required for the building of a start-up, starting from the development of a brilliant idea, exploration of the market, building of a financial model and a business plan The teaching material of the training weeks has been uploaded on a secure section of the project webpage for future access by the ESRs. Furthermore, the ESRs implemented several trans-national secondments in academia and industry which enhanced their knowledge, mobility and “European” spirit.

The research activities of the EuroNeurotrophin project enabled the generation of new knowledge in the area of neurotrophin mimetics. The research is implemented through three work packages. In WP1 extensive molecular docking studies and simulations were performed to understand the binding to neurotrophin receptors, and in silico screening of the UNICAEN library of 18000 compounds led to the selection of potential neurotrophin agonists. Additionally, fractionation of 85 bacterial and 15 fungal strains of marine origin and synthesis of a number of new mimetics was effected. Furthermore, the expression of recombinant neurotrophin receptors is ongoing for structural biology studies. In WP2 the in vitro high- and low-throughput biological evaluation of all the different natural and synthetic compounds and extracts was performed, which led to selection of potent agonists for neurotrophin receptors TrkA, TrkB and p75NTR, and compounds inhibiting neuroinflammation. In WP3 proteomic studies of the temporal effect of the new neurotrophin mimetics on synapse proteome and synapse density using mice models are ongoing.

A key EuroNeurotrophin dissemination strategy during the first reporting period, has been the presenting of project results in the form of talks and posters at key international conferences, workshops, seminars and other relevant events. In total, EuroNeurotrophin results and outcomes were disseminated with 7 presentations and 17 posters at international conferences. ESR 2 and ESR6 received awards for their poster presentations. Furthermore, two open access scientific publications were produced.
The project presence on social network platforms has been established to reach a greater number of pharma market professionals and the general public. EuroNeurotrophin currently has a YouTube and Twitter account, a ResearchGate project and a LinkedIn group which are managed by the ESRs. Each ESR has created a 1-page Fiche to present their individual research projects. Finally, participation of the ESRs in 8 networking events and 7 local public engagement events have increased the project visibility to the general public, students and relevant stakeholders.
EuroNeurotrophin meets the emerging need for training researchers in drug discovery and development with a focus on the design, synthesis and isolation of new neuroprotective small molecule neurotrophin mimetics and their assessment using multimodal approaches, as well as their use towards market applications. Furthermore, research results to date have contributed to the field of neurotrophin mimetics expanding the chemical space of the available structural motifs and sources (natural and synthetic) resulting in the further development and understanding of small agonists of neurotrophin receptors. These leads will have the potential to provide new therapeutic agents that can prevent, treat or ameliorate the onset and progression of neurodegenerative diseases and/or neuroinflammation via the neurotrophin receptors.
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