Small Molecule DNA Rotaxanes

Oligonucleotides (ONs) such as DNA are on the rise as a benign method to regulate cellular function and treat difficult diseases. One of the key challenges in ON-based treatments is the stability of ONs since the phosphates in the backbone are cleaved by enzymes. Here, it is proposed to develop a new type of rotaxanes, where small cyclic molecules with a positive charge are locked around the negatively charged phosphate groups in the ON backbone without chemical bonds to the ON, and the rings are too small to slide off. This will protect the ON, whether DNA or RNA, against degradation and neutralize the charge of the ON. Thereby, delivery of ON drugs will become much more feasible. The rings will be locked with a disulfide bond, which is stable outside the cell, but is opened once the supramolecular structure enters the reductive environment in the cell. Thus, the pristine ON will be released inside the cell and execute its function.