Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazine­carboxamide Pseudobase T‑705 and Its De-Fluoro Analogue T‑1105 as Potent Influenza Virus Inhibitors

We
here disclose chemical synthesis of ribonucleoside 5′-monophosphate
(RMP), -diphosphate (RDP), and -triphosphate (RTP) and cycloSal-, DiPPro-, and TriPPPro nucleotide
prodrugs of the antiviral pseudobase T-1105. Moreover, we include
one nucleoside diphosphate prodrug of the chemically less stable T-705.
We demonstrate efficient T-1105-RDP and -RTP release from the DiPPro and TriPPPro compounds by esterase
activation. Using crude enzyme extracts, we saw rapid phosphorylation
of T-1105-RDP into T-1105-RTP. In sharp contrast, phosphorylation
of T-1105-RMP was not seen, indicating a yet unrecognized bottleneck
in T-1105’s metabolic activation. Accordingly, DiPPro and TriPPPro compounds displayed improved cell
culture activity against influenza A and B virus, which they retained
in a mutant cell line incapable of activating the nucleobase parent.
T-1105-RTP had a strong inhibitory effect against isolated influenza
polymerase, and DiPPro-T-1105-RDP showed 4-fold higher
potency in suppressing one-cycle viral RNA synthesis versus T-1105.
Hence, our T-1105-RDP and -RTP prodrugs improve antiviral potency
and achieve efficient metabolic bypass.