Periodic Reporting for period 1 - bioTARGET (Bioorthogonal Cascade-Targeting: Directing Drugs into Cells with Molecular Precision)
Okres sprawozdawczy: 2023-01-01 do 2025-06-30
The precise delivery and controlled activation of therapeutic agents within specific cells remain among the most pressing challenges in modern medicine. Although many therapeutic molecules are highly potent, their clinical effectiveness is often limited by poor selectivity and suboptimal localization, leading to unwanted side effects or insufficient activity at the target site. One promising avenue to address these limitations is the use of bioorthogonal chemistry, a powerful approach that allows chemical reactions to proceed inside living systems without interfering with natural biological processes. So far, most bioorthogonal strategies have been limited to single-step transformations, such as molecular ligations for labeling or the release of drugs through endpoint cleavage reactions. While these approaches have led to important advances, they remain inherently static and are not designed to control the dynamic movement of molecules within complex biological environments. As a result, the selective shuttling of therapeutic agents into specific cells and their timely activation within distinct intracellular compartments remains a largely unmet need. The ERC-funded project bioTARGET aims to introduce the concept of bioorthogonal navigation, a new approach that seeks to guide molecules through biological systems using carefully programmed chemical reactions. By designing chemical tools that operate as controlled cascades, the project seeks to trigger sequences of molecular events from a single initiating bioorthogonal reaction. These cascades are engineered to proceed safely and efficiently under physiological conditions and are enabled by newly developed cleavable linkers and activatable ligands with exceptional reactivity and precision. Through these innovations, bioTARGET will expand the chemical scope of bioorthogonal bond-cleavage reactions and enable a new level of control over the spatial and temporal behavior of molecules in cellular environments.
The project focuses on the development of chemical tools and molecular systems required to implement cascade-targeting strategies based on bioorthogonal chemistry. A key achievement has been the development of a next-generation cleavable linker, iTCO, which enables ultrafast and efficient click-to-release reactions under physiological conditions. This tool is central to all planned strategies and sets a new standard for reaction performance in the field. Building on this platform, we developed the concept of tandem release, a sequential bond-cleavage cascade triggered by a single chemical event. This transformation significantly expands the functional scope of bioorthogonal chemistry and provides new opportunities for controlled molecular activation in living systems. In addition, we discovered a highly reactive cleavable linker, scTCO, with strong potential for applications in bioorthogonal prodrug activation. Alongside tool development, we made significant progress in applying these technologies to molecular targeting. Activatable ligands were designed and synthesized to explore bioorthogonal control over cellular uptake and sequential targeting, laying the groundwork for the project’s broader objectives.
The project has generated several key innovations that go beyond the current state of the art in bioorthogonal chemistry, most notably the development of iTCO and tandem release systems, which enable ultrafast, tunable, and multi-stage molecular activation in living systems. These advances provide new opportunities for precise drug delivery, molecular imaging, and targeted therapeutic activation. The discovery of scTCO, a highly reactive cleavable linker, offers additional translational potential in the context of prodrug activation. To fully realize the impact of these technologies, further research into biological applications is ongoing, and IP protection has been initiated. Future uptake will benefit from targeted Proof of Concept studies, regulatory awareness, and strategic partnerships.