Periodic Reporting for period 2 - EuroNeurotrophin (A European training network for the discovery of neurotrophins small molecule mimetics as candidate therapeutic agents for neurodegeneration and neuroinflammation)
Période du rapport: 2020-01-01 au 2022-03-31
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, mainly because of their sensitivity to proteolysis, restricted penetration of the blood–brain barrier, and limited ability to diffuse in tissues, 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 5 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 were 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.
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, mainly because of their sensitivity to proteolysis, restricted penetration of the blood–brain barrier, and limited ability to diffuse in tissues, 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 5 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 were 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.
The EuroNeurotrophin project provided a multidisciplinary training program to the ESRs with the aim to increase their knowledge within a targeted scientific context and their formation as highly valued scientists with high level employment perspectives. Local training courses and workshops were selected based on the needs and interests of the fellows. The network-wide three Training Weeks encompassed three Schools on in silico drug design and biomolecular NMR screening in drug discovery, modern synthetic methodologies leading to neurotrophin mimetics, in vivo models for neurodegenerative disorders and structural biology approaches for neurodegeration. These were complemented by an array of workshops and courses on highly desirable technical and transferable skills. 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 knew knowledge in the area of neurotrophin mimetics. The research was implemented through three work packages. In WP1 extensive molecular docking studies and simulations were performed to understand the binding to neurotrophin receptors, in silico screening of the UNICAEN library of 18000 compounds led to the selection of potential neurotrophin agonists, fractionation of 85 marine bacterial and 15 fungal strains led to the isolation of 80 secondary metabolites while, the synthesis of >80 new mimetics was effected. Furthermore, crystallization studies with expressed and purified TrkA and TrkB ectodomains with the new mimetics were performed. BMECs were successfully differentiated from human induced pluripotent stem cells in both, healthy and amyotrophic lateral disease (ALS) context. A Tau double mutant P301L/S320F in vitro model for neurotrophic mimetic testing in neurodegenerative diseases was developed. In WP2 the in vitro high- and low-throughput biological evaluation of all the different natural and synthetic compounds and extracts was performed, using cells, mature neurons and neural stem cells 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 were studied while, two lead compounds were tested in vivo in the LPS-induced neuroinflammation and 5xFAD mouse models.
The EuroNeurotrophin dissemination strategy included presenting the project results at key international conferences, workshops, seminars and other relevant events. In total, EuroNeurotrophin results and outcomes were disseminated in 61 conferences and 16 workshops. The highlight was the International Conference on “Neurotrophic factors and neurodegenerative disorders; current advances and future perspectives" organized by the consortium in Crete that concentrated many of the key players in neurotorphin research and was attended by 240 participants.
The project presence on social network platforms was 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 within EuroNeurotrophin. 3 Newsletters were disseminated while, participation of the ESRs in 41 networking and local public engagement events have increased the project visibility to the general public, students and relevant stakeholders.
The research activities of the EuroNeurotrophin project enabled the generation of knew knowledge in the area of neurotrophin mimetics. The research was implemented through three work packages. In WP1 extensive molecular docking studies and simulations were performed to understand the binding to neurotrophin receptors, in silico screening of the UNICAEN library of 18000 compounds led to the selection of potential neurotrophin agonists, fractionation of 85 marine bacterial and 15 fungal strains led to the isolation of 80 secondary metabolites while, the synthesis of >80 new mimetics was effected. Furthermore, crystallization studies with expressed and purified TrkA and TrkB ectodomains with the new mimetics were performed. BMECs were successfully differentiated from human induced pluripotent stem cells in both, healthy and amyotrophic lateral disease (ALS) context. A Tau double mutant P301L/S320F in vitro model for neurotrophic mimetic testing in neurodegenerative diseases was developed. In WP2 the in vitro high- and low-throughput biological evaluation of all the different natural and synthetic compounds and extracts was performed, using cells, mature neurons and neural stem cells 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 were studied while, two lead compounds were tested in vivo in the LPS-induced neuroinflammation and 5xFAD mouse models.
The EuroNeurotrophin dissemination strategy included presenting the project results at key international conferences, workshops, seminars and other relevant events. In total, EuroNeurotrophin results and outcomes were disseminated in 61 conferences and 16 workshops. The highlight was the International Conference on “Neurotrophic factors and neurodegenerative disorders; current advances and future perspectives" organized by the consortium in Crete that concentrated many of the key players in neurotorphin research and was attended by 240 participants.
The project presence on social network platforms was 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 within EuroNeurotrophin. 3 Newsletters were disseminated while, participation of the ESRs in 41 networking and 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.