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

著者: Jeong-Joong Yoon, Märt Toots, Sujin Lee, Myungeun Lee, Barbara Ludeke, Jasmina M. Luczo, Ketaki Ganti, Robert M. Cox, Zachary M. Sticher, Vindya Edpuganti, Deborah G. Mitchell, Mark A. Lockwood, Alexander A. Kolykhalov, Alexander L. Greninger, Martin L. Moore, George R. Painter, Anice C. Lowen, S. Mark Tompkins, Rachel Fearns, Michael G. Natchus, Richard K. Plemper - Antimicrobial Agents and Chemotherapy 2018 被引用: 245

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 an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 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 of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens 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 is a promising candidate for future clinical development as a treatment option for influenza-like diseases.