Project description
Understanding cellular processes and protein therapeutic potential
Chemical biology has advanced in recent decades, leading to effective inhibitors for key drug target proteins, particularly G protein-coupled receptors (GPCRs). However, research has focused on inhibition. It is also important to explore the potential of small molecules to activate enzymes, alter post-translational modifications (PTMs), or control the oligomeric state of proteins. The ERC-funded CovProximity project aims to harness small molecules to expand biochemical perturbations and PTMs in cells, enhancing our understanding of cellular processes and their therapeutic potential. Building on Covalent Ligand-Directed Release (CoLDR) chemistry, the project will develop CoLDR-based probes for various protein targets, enabling selective perturbation of novel substrates, promoting homo-dimerisation, and facilitating the modification of targets both in vitro and in cells.
Objective
Chemical biology has made remarkable strides over recent decades, producing potent and selective inhibitors for many proteins, including essential drug targets. Despite these achievements, however, inhibition has been the primary mode of perturbation (GPCRs notwithstanding), whereas many biological processes are controlled through a rich spectrum of biochemical perturbations. What if a small molecule could activate an enzyme? Install or remove a post-translational modification (PTM)? Or control its oligomeric state?
The overarching goal of this proposal is to dramatically increase the scope and breadth of perturbations and PTMs one can induce in cells using small molecules. Accomplishing this will have tremendous impact on the ability to investigate numerous cellular processes and holds massive therapeutic potential.
To achieve this goal, we will build on our recently developed Covalent Ligand-Directed Release (CoLDR) chemistry, which allows to
tag proteins covalently while preserving their function. Our research will develop:
1. a general method to create CoLDR-based probes against a panel of targets, that would enable us to harness their activity for
selective perturbation of new, non-endogenous, substrates.
2. homo-dimeric CoLDR probes to induce selective dimerization of targets. This will allow us to selectively activate targets such as
kinases in cells. We will also design protein polymerizers, by tethering obligatory homodimers.
3. chimeric proximity inducers that would selectively modify new targets in vitro and in cells.
Our group’s experience in covalent chemical biology, proteolysis-targeting chimeras, and the development of the CoLDR platform,
makes us uniquely positioned to create the next generation of covalent proximity inducers.
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)
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)
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Call for proposal
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(opens in new window) ERC-2023-COG
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7610001 Rehovot
Israel
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