Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

Ribo-cytidine and adenosine analogs containing a methyl group at the 2 0 -position on the ribose are known inhibitors of HCV and other related members of the Flaviviridae family. [113] [114] [115] [116] [117] [118] [119] One of the most potent molecules of this series, 7-deaza-2 0 -C-methyladenosine (7DMA, MK-0608), was once a development candidate for the treatment of HCV infection ( Figure 5) . 117, 120 The adenosine analog 7DMA also inhibits HRV type A infection in vitro, with EC 50 values ranging from 2 to 12 mM. 121 A subgenomic replicon assay was used in transient transfection experiments to demonstrate that 7DMA is equipotent against multiple strains of HRV type C. This important proof-of-concept experiment demonstrated that 2 0 -methyl nucleosides prevent picornavirus replication, most likely by inhibiting the viral RNA polymerase function. This class effect was confirmed with NITD008, another adenosine analog containing a 2 0 -C-ethynyl on its 2 0 -ribose ( Figure 5 ). Just like 7DMA, NITD008 was previously known to inhibit Flaviviruses, and was once a development candidate for the treatment of dengue infection. 122 NITD008 blocks the replication of dengue virus in cell culture and in mice by inhibiting the RdRp activity of the NS5 protein. 122, 123 Therefore, the possibility that NITD008 would inhibit other (þ)ssRNA viruses is not unexpected. Indeed, NITD008 blocks the replication of EV71, another enterovirus-related to rhinovirus. 124 This in vitro antiviral effect was confirmed in a separate study that also demonstrated in vivo efficacy. 125 Investigators in the latter study infected 2-week-old AG129 immunocompromised mice with EV71 by intraperitoneal inoculation. Treatment of the infected animals with NITD008 given orally at 5 mg/kg twice a day for 4 days resulted in 100% survival at the end of the study, compared to 0% survival for the vehicle control group. NITD008 cannot be developed in the clinic due to severe toxicity seen in 14-day studies in rats and dogs. 122 However, the results summarized here indicate that nucleoside analogs targeting the viral RNA polymerase of rhinovirus, EV71, and other enteroviruses have the potential to be efficacious in preclinical animal models, providing a rationale to conduct human studies with safer molecules sharing the same mode of action.