Project description
New drug discovery for intrinsically disordered proteins
Intrinsically disordered proteins (IDPs) pose a challenge in drug discovery. These elusive proteins defy traditional targeting methods due to their lack of well-defined binding sites for small molecules. However, a solution is now on the horizon. The ERC-funded PPI-Glue project targets molecular glues, a cutting-edge technology capable of strengthening protein-protein interactions (PPIs). At the heart of this endeavour is the hub protein 14-3-3, known to regulate numerous IDPs through phosphorylation-dependent PPIs. By stabilising these interactions with small molecular glues, PPI-Glue opens new doors to make IDPs druggable and combat malfunctions in diseases like neurodegeneration. Aiming to understand the process and drug the undruggable, this project could pave the way for novel drug discovery in the fight against neurodegenerative diseases.
Objective
Intrinsically Disordered Proteins (IDPs) represent one of drug discovery’s major challenges. Due to their high degree of conformational freedom, IDPs have no defined pockets for binding small molecules. Molecular glues that can strengthen protein-protein interactions (PPIs) are a revolutionary technology for drug discovery. The hub protein 14-3-3 regulates many IDPs via phosphorylation-dependent PPIs. Stabilization of 14-3-3 PPIs with small molecular glues provides a unique entry point to render IDPs druggable and mitigate the aberrant behaviour of malfunctioning IDPs, for example in neurodegenerative diseases.
While inhibition of PPIs by small molecules has expanded the proteome suitable for therapeutic intervention, the opposite chemical-biology strategy of PPI stabilization by small molecular glues is, despite a recent surge of interest, remarkably underexplored. The lack of mechanistically understanding PPI stabilization impedes systematically identifying molecular glues and limits progress to drug IDPs. Based on compelling preliminary data, I propose here that mechanistic understanding of 14-3-3 PPI stabilization will play a crucial role in the discovery of molecular glues for IDPs and transform molecular glue drug discovery from art into science.
We will tackle this central question by pursuing two key objectives: Objective 1 – Mechanistically understand PPI stabilization between the 14-3-3 scaffold protein and IDPs. This will address the underlying thermodynamic and kinetic processes, conformational selection, multivalency, cooperativity and selectivity; Objective 2 –Drugging the undruggable -biomolecular condensates and IDPs- via PPI stabilization approaches. The potential for PPI stabilization in the dense environments of biomolecular condensates will be uncovered and a mechanism-driven campaign to identify molecular glues for the 14-3-3/Tau PPI will lead the way to novel drug discovery for neurodegenerative diseases.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2022-ADG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
5612 AE Eindhoven
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.