Membrane-Permeable Nucleoside T-1106 Diphosphate and Triphosphate Analogues as Antiviral Pronucleotides

The nucleobase T-1105, the non-fluorinated analogue of favipiravir (T-705), inhibits viral RNA synthesis after conversion to its ribonucleoside-5'-triphosphate (T-1105-RTP) metabolite. However, this metabolic activation is rate-limiting and inefficient. We here report the chemical synthesis and evaluation of three series of T-1105-ribonucleoside (T-1106)-DiPPro- and TriPPPro-nucleotide prodrugs to allow their cellular uptake. Their efficient release of the T-1106-diphosphate and triphosphate forms was demonstrated upon incubation in PBS, pig liver esterase, extract of human T-lymphoblast CEM/0 cells and human plasma. This validates the successful hydrolysis and delivery of the corresponding nucleotides, via chemical or enzyme-triggered mechanisms. Interestingly, several T-1106-DiPPro-prodrugs, for example, compound 24h, and TriPPPro-prodrugs proved superior to the parent T-1106 nucleoside, in inhibiting influenza A and influenza B replication in MDCK cells, and of human coronavirus OC43 in HEL299 cells. This validates the utility of our pronucleotide strategy to overcome the inefficient activation of T-1106 and increase the antiviral efficacy against influenza and coronaviruses.