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Curation, Integration, Modelling and Rational Design of Small Molecule Amyloid Inhibitors

Cel

Protein aggregation is a major concern in biomedical research as this mechanism is responsible for at least 40 increasingly common human disorders, including Parkinson's disease, Alzheimer's disease, Huntington’s disease, Amyotrophic lateral sclerosis and certain types of cancer or type II diabetes. These protein aggregates can be isolated from patients in the form of amyloid depositions. Environmental conditions, such as pH, temperature, the interaction with other proteins, lipids or nucleic acids, the formation of phase-separated compartments or the presence of small molecules, influence the aggregation reaction. Until recently, the only available treatment for amyloidosis was palliative care. Fundamental research has identified small molecules from several hundred thousand different molecular entities and developed antibodies that delay amyloid conversion, leading to disease-modifying therapeutics for some of these pathologies. Yet prioritising the best candidates has led to overlooking the precise chemical and pharmacophoric determinants necessary to inhibit or delay aggregation for each protein variant. By manual curation of decades-long peer-reviewed knowledge, extraction and annotation of the effects of these multiple thousands of molecular entities, we will construct a database with aggregation-inhibiting and non-inhibiting molecules for each pathological protein. This data will be used to train a machine learning model that defines the chemical fingerprints required for preventing aggregation in each proteotype. The model will allow us to identify chemical entities not previously assayed, repurpose existing ones and design novel molecules. The most promising hits will be synthetised and experimentally assayed in vitro. Overall, this project represents a paradigm change to transition from the time and resource-costly trial-and-error screening toward a rational design of disease-modifying therapeutics.

Dziedzina nauki (EuroSciVoc)

Projekt nie został jeszcze sklasyfikowany według klasyfikacji EuroSciVoc.
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Słowa kluczowe

Program(-y)

Temat(-y)

System finansowania

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Zaproszenie do składania wniosków

(odnośnik otworzy się w nowym oknie) HORIZON-MSCA-2025-PF

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Koordynator

VILNIAUS UNIVERSITETAS
Wkład UE netto
€ 196 976,16
Koszt całkowity
Brak danych