Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses [PublishAheadOfPrint]

Morbidity and mortality resulting from influenza-like disease are a threat especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics are urgently needed that are efficacious against major drivers of influenza-like disease including influenza viruses and respiratory syncytial virus (RSV). Using a dual-pathogen high throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified N⁴-hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses and IAVs of human, avian, and swine origin. Biochemical in vitro polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36-56%, sustained levels of the active 5'-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAV in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burden in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC a promising candidate for future clinical development as a treatment option for influenza-like diseases.

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