Project description
Targeting specific protein forms within cells
Although we have about 20 000 protein-coding genes, the human body can produce more than one protein variation from each gene. The diversity of proteins present in the human body increases through complex processes such as alternative mRNA splicing and post-translational modifications. Given that changes in specific proteins have been associated with cancer and neurogenerative diseases, it is crucial to understand the underlying mechanisms. The ERC-funded PROTEOFORMER project aims to develop chemical tools that can precisely manipulate selected protein forms inside cells. The project focuses on a brain receptor implicated in Parkinson’s disease and a key regulator of neuroinflammation. By adding functional chemical cargo directly to chosen protein forms, researchers will selectively inhibit or switch between protein forms.
Objective
The human body can synthesize ~70’000 different proteins. These proteins diversify into millions of proteoforms, e.g. by associating into complexes or acquiring functionalities called post-translational modifications (PTMs). Distinct proteoforms are often found in different cell types and have diverse functions. Dysregulation of specific proteoforms is associated with many diseases, including neurodegeneration or cancers, highlighting the need for their study and modulation. Despite these needs, most drug-like molecules are designed to indiscriminately activate, inhibit, or destroy a target protein—they are blind to the localization or function of different proteoforms.
PROTEOFORMER goes beyond the protein by developing chemical tools for manipulating specific protein forms. In two parallel initiatives, PROTEOFORMER will:
(1) Target a specific proteoform of the muscarinic acetylcholine receptor—relevant to Parkinson’s disease treatment—dissecting its function and laying the groundwork for new therapies.
(2) Modify post-translational modifications of matrix metalloproteinase-2—a key regulator of neuroinflammation—aiming to unravel their so-far-elusive function.
PROTEOFORMER offers tailored reagents that (i) recognize the protein target, (ii) bring a reactive group to the target’s surface, and (iii) attach molecular cargo to the protein via a proximity-induced reaction. It rethinks this ‘ligand-directed chemistry’ by introducing functional, proteoform-manipulating cargo:
(1) A blocker of a partner protein, enabling proteoform-selective inhibition within a cell-specific complex.
(2) A post-translational modification or its eraser, enabling on-demand switching between proteoforms with newly developed proximity-driven chemical reactions.
PROTEOFORMER develops new chemistry for manipulating proteoforms beyond current capabilities. These general concepts represent a chemical solution to long-standing challenges in biology that are intractable with traditional methods.
Fields of science (EuroSciVoc)
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2025-STG
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601 77 Brno
Czechia
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