Galactosidase-activatable (“frosted”) oligonucleotides

• Applicant: Professor Dr. Alexander Heckel
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558312878

In the design of biologically active compounds, selectivity is of utmost importance. This can for example be target selectivity or delivery selectivity and, in this context, especially the control of when and where the compound is active. In our previous work we have addressed the latter with light as external trigger signal and prepared a host of light-activatable and hence conditionally active oligonucleotides. While light as a trigger signal is very elegant and versatile, there are applications where oligonucleotide-based approaches need to be selective but are not restricted to a certain area but rather to a different selection criterion as for example a certain cell type or cell stage. Furthermore, the application of light is also limited by the location of the target region, and not all tissues can easily be reached with light. Examples for a “liquid tumor" are acute leukemias which can e.g. be targeted with the regulation of miRNAs. This calls for a cell-intrinsic internal trigger signal to avoid the adverse effects of a systemic miRNA regulation. We propose to use galactosidase-levels as trigger signal as it is known that in senescent cells and in certain tumor cells these levels are increased.

• DFG Programme: Research Grants