The increasing prevalence of viral and microbial infections calls for effective drugs. Unnatural nucleosides seem to be a very strong candidate for antiviral drugs, and a lot of research is being done in this area. One example is the recently published research by the Universities of Parma, Siena, Liège and KU Leuven on such unnatural nucleosides, which show broad applicability against both viruses and bacteria.

Earlier research by the Italians had already identified antiviral variants of purine, the nucleobase you also find in your DNA in the form of guanine and adenine. They linked these modified 2,6-diaminopurines to ribose, modified the resulting nucleosides here and there, and then tested them for activity. Some of the variants showed activity against Zika, West Nile, dengue and SARS-CoV-2 viruses at relatively low micromolar concentrations. The same was true for a range of gram-positive and -negative bacteria.

The researchers made a prodrug (ProTide) of the best variant to see exactly how it worked, but when they tested it, it lost all activity. They therefore believe that the mechanism is different from that of other antiviral nucleosides.

With this research, the team also wanted to take a first step towards drugs with two mechanisms of action. After all, the reaction between the unnatural nucleosides and a cell itself produces activity, but if you can then remove the purine by breaking the glycosidic bond, you could use that too to fight viruses. The researchers had to report that they themselves had not been successful, but they are already working on this as part of follow-up research.

Grazia Martina, M. et al. (2023) ChemMedChem e202300200, DOI: 10.1002/cmdc.202300200