H2020Индивидуална стипендия2020–2022

MTD4ALS · Development of inovative multi-target drugs for ALS

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-06-01 → 2022-05-31
Финансиране от ЕС: 159 815 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Разработват се нови лекарства, които едновременно намаляват възпаленията в нервната система и премахват излишното желязо от тъканите. Това е важно, защото сегашните терапии при амиотрофичната странична склероза (ALS) само леко забавят симптомите или удължават живота за няколко месеца.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Development of inovative multi-target drugs for ALS

Motor Neuron Disorders (MNDs) are a heterogeneous group of diseases characterised by the progressive loss of motor neurons (MNs). Among them, Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset form of MND. ALS is characterized by the progressive loss of MNs responsible for the voluntary movements in the motor cortex and in the spinal cord of the patients and dia due to respiratory failure 3-5 years after diagnosis. Nevertheless, there is no cure available for the ALS, and the two only drugs approved for ALS treatment, Riluzole and Edaravone are only capable of, respectively, increasing patient survival (3-4 months) and delay the progression of symptoms in the initial stages of the disease. Therefore, is not surprising that due to the high social and economical burden of ALS that there is tremendous pressure from the patients and their families, and the global healthcare system for the development of more efficient therapies. ALS is a multifactorial disease characterised by defects in several biological mechanisms such as mitochondria homeostasis, antioxidant response or inflammation that contribute to the disease progression. Hence, to surpass the past failures the development of small molecules capable to modulate multiple pathways in ALS may provide prime tools for the development of new and better pharmacological therapies than the drugs currently accessible to the patients. Following this rationale in this action, we proposed the development of a therapeutic approach based on small molecules capable to modulate NF-kB transcription factor activity (a key player in neuroinflammation) and, with iron chelation properties to minimize the negative effects of the abnormal iron accumulation in the patient tissues (Fenton/Haber-Weiss reactions and ferroptosis) and trigger cell-survival mechanisms through mild HIF stabilization.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Amyotrophic Lateral Sclerosis is a severe neurodegenerative disease characterized by the degeneration of the upper and lower motor neurons (MN), ultimately leading to patient death by respiratory failure. Despite being the most common adult-onset motor neuron disease, the drugs available till now are symptomatic and only extend patients life expectancy a few months without changing the onset of the disease. Recent studies revealed that NF-κB transcription factor is the major regulator of neuroinflammation in ALS. Therefore, inhibitors of NF-κB signalling pathway can be considered key tools for the development of novel therapies for ALS. Additionally, the use of iron chelators have also shown potential to increase ALS survival through the regulation of iron redox activity and by triggering MN cell survival mechanisms through the mild activation of HIF transcriptional factor. In this project we propose an innovative therapeutic solution for ALS based on the design and syntheses of multitarget small-molecules capable to modulate NF-κB activity through inhibition of IKKβ protein and prevent/minimize the iron induced oxidative damage and/or stabilize HIF. The project encompasses the rational design and synthesis of a library of small molecules that will be submitted to an initial cascade of biophysical and chemical assays to evaluate their binding affinity and iron chelation properties. Subsequently ALS cellular models will be used in order to validate target engagement inside cells, as well as, to identify the small-molecules that could protect MN from oxidative-stress and inflation driven apoptosis. At the end of the project it is expected to propose a novel lead compound that will be optimized and its performance evaluated in ALS animal models. This project combines the expertise available in academia and industry to validate a new therapeutic approach for ALS and, provides an exceptional training opportunity to prepare a young researcher for his future career.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSIDADE DO PORTO · PortoКоординаторПортугалия