Rotaxane-Oligonucleotides: Stimuli-Responsive Mechanically Interlocked Architectures to Control Oligonucleotide Activity and Gene Transcription

Ziel

Recently, DNA-mimics have been developed in which a natural phosphate unit linking the DNA bases is replaced with a non-natural triazole. This DNA-mimic behaves identically to natural DNA, presenting an opportunity I will exploit during this Fellowship: my mentor, Prof Goldup, has developed chemistry that wraps a ring-shaped molecule (macrocycle) around such triazole links to produce interlocked molecules called rotaxanes. These molecules are perhaps most famous as components of molecular machines, culminating in the 2016 Nobel Prize for chemistry part-awarded to Stoddart and Sauvage, but the mechanical bond also offers opportunities to control the chemistry of the interlocked components.

Combining these approaches, I will create interlocked rotaxane-DNAs to study how threading the macrocycle onto DNA affects the biological function of the nucleic acid. During this Fellowship I will develop the first generation of rotaxane-oligonucleotides, study their properties and utilize the mechanical bond to regulate their biological activity. These interlocked oligonucleotides will be demonstrated as versatile new tools for chemical biology through examples of controlled gene expression and therapeutic siRNA applications.