Streamlining the route of phosphonate XNA from chemistry to application

Synthetic oligonucleotides (ON) have a broad potential for applications in diagnostics, therapeutics and storage of genetic material. The poor enzymatic and chemical stability of natural nucleic acids urged the development of synthetic or xenobiotic nucleic acids (XNAs) that are more stable. Depending on the application, interaction of XNA with natural nucleic acids is required (complementary XNA) or should be avoided (orthogonal XNA). This project focusses on the new class of ON with phosphonate instead of phosphate-linked nucleosides providing increased stability. Several constructs will be explored with ‘sugar’ units varying from an open chain over five membered ring systems towards six membered ring systems replacing the native ribose in the nucleic acid backbone to obtain a range of XNA with increasing orthogonality. Toxicity of the phosphonate nucleoside building blocks is expected to be limited as they are close relatives a Tenofovir, a widely used antiviral drug. While selected phosphonate ON became recently chemical accessible, this project will yield knowledge and tools that bridge the gap to the level of applications.

Keywords:XNA, phosphonate, diagnostics, biotechnology, therapeutics

Disciplines:Medicinal chemistry, (Bio)molecular modelling and design, Synthetic biology, Bio-organic chemistry, Characterisation of biologically active (macro)molecules, Nucleic acids