Objective
Bioorthogonal click-to-release chemistry enables selective bond cleavage in complex biological environments and has emerged as a powerful concept for controlled prodrug activation, most prominently through trans-cyclooctenes and tetrazines. However, established systems face trade-offs between reaction speed, release efficiency, and stability, limiting their application in therapeutic settings. We have discovered a strained cleavable trans-cyclooctene linker that uniquely combines ultrafast click kinetics with high release efficiency and stability. Compared to current approaches, this TCO exhibits more than 20-fold faster click reactivity, enabling activation under conditions not accessible with existing methods. This advance enables efficient prodrug activation even at nanomolar concentrations, opening new possibilities for targeted therapeutic strategies that remain out of reach. The project will establish proof of concept by developing TCO-caged prodrugs of clinically relevant therapeutics and validating this process using tetrazine triggers, including scaffolds already advanced to clinical trials. Release kinetics, stability in biological media, and biological activity will be systematically evaluated in solution and cellular models. A central concept of the project is click accumulation, where ultrafast kinetics enable local capture and activation of circulating prodrugs. This will be demonstrated in microfluidic models that mimic vascular flow, providing evidence for efficient activation and therapeutic efficacy at low systemic concentrations. Supported by an initial patent filing, this technology represents a versatile platform with strong translational potential. It is expected to create new opportunities for safer and more effective targeted therapeutics, with potential applications in prodrug strategies and related delivery systems.
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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)
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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-POC - HORIZON ERC Proof of Concept 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-2026-POC
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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.
1040 Wien
Austria
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.