Synthesis and characterization pyrimidine C-nucleoside phosphonates as a new class of RNA nucleotide mimics with therapeutic potential
Nucleoside therapeutics are a class of pharmaceutically relevant molecules that exhibit a broad spectrum of clinical applications. This project will generate and explore a new class of phosphonate nucleoside analogues based on pyrimidine C-nucleosides. A new ‘in cell’ NMR approach will be developed to monitor cellular uptake and metabolism of phosphonate nucleosides. Prior to application on new molecules, this 31P-based method will be established and validated on a nucleoside phosphonate with known metabolism (tenofovir alafenamide). Suggested new compounds combine the advantages of C-nucleoside analogues to those of nucleoside phosphonate chemistry and are designed to target enzymes which are crucial in RNA metabolism of viruses and bacteria. Development of antibiotics that tackle a crucial step the bacterial life cycle in an unexplored manner is an essential approach in the discovery of new antibiotics without cross-resistance with existing therapeutics. Outbreaks of SARS, MERS and COVID-19 painfully demonstrated that the family of RNA-viruses is not sufficiently covered by anti-viral drugs that are available nowadays. Proposed molecules could hopefully help to fill this gap.