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Computer-Aided Drug Design for Bridge-like Lipid Transfer Proteins

Objective

Recently, the discovery of a family of large proteins, now called bridge lipid transport proteins (BLTPs), that can act as “bridges” for lipids to flow between organellar membranes, has revolutionized how we think about bulk lipid movement in cells, which was previously thought to take place mainly via vesicular trafficking. These proteins are components of lipid transfer machines that participate in de novo formation of cellular organelles and/or in membrane expansion or repair.
Dysfunction in human BLTPs is causative of severe neurological diseases such as an early onset version of Parkinson’s (VPS13C), chorea acanthocytosis or Cohen syndrome. In addition, expression levels of certain BLTPs correlate with cancer aggressiveness, and BLTPs can also exploited by pathogens, for example to form their replication compartments. Currently, no drug treatment targeting BLTPs exists, including in clinical trials, in large part due to the scarcity of information about BLTP mechanism and structural features.
During my ERC Grant MCS-MD, we have largely progressed in our basic understanding of BLTP-mediated molecular mechanism, including the discovery of new membrane protein partners that bind BLTPs and anchor them at surrounding membranes, as well as the characterisation of entire BLTP complexes at high-resolution using cryo-electron microscopy. These very recent discoveries open exciting opportunities to undertake computer-assisted drug-design (CADD) screening efforts to investigate the interaction of BLTP complexes with existing drugs (repurposing) or to use AI-assisted structural strategies to design new small molecules or proteins that can inhibit or enhance BLTP activity. These efforts will lead to the identification of potential drug leads that we will subsequently test in reconstituted systems and in human cell lines. Overall, our drug screening protocol will move us closer towards the development of therapeutic strategies and interventions benefitting human health.

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HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

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(opens in new window) ERC-2025-POC

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Host institution

UNIVERSITE DE FRIBOURG
Net EU contribution

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€ 150 000,00
Address
AVENUE DE L EUROPE 20
1700 Fribourg
Switzerland

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Region
Schweiz/Suisse/Svizzera Espace Mittelland Fribourg / Freiburg
Activity type
Higher or Secondary Education Establishments
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Total cost

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Beneficiaries (1)