Synthesis and Metabolic Studies of Host Directed Inhibitors for Anti Viral Therapy.
Moore TW, Sana K, Yan D, Krumm SA, Thepchatri P, Snyder JP, Marengo J, Arrendale RF, Prussia AJ, Natchus MG, Liotta DC, Plemper RK, Sun A.
Targeting host cell factors required for virus replication provides an alternative to targeting pathogen components and represents a promising approach to develop broad-spectrum antiviral therapeutics. High-throughput screening (HTS) identified two classes of inhibitors (2 and 3) with broad-spectrum antiviral activity against ortho- and paramyxoviruses including influenza A virus (IAV), measles virus (MeV), respiratory syncytial virus (RSV), and human parainfluenza virus type 3 (HPIV3). Hit-to-lead optimization delivered inhibitor, 28a, with EC50 values of 0.88 and 0.81 μM against IAV strain WSN and MeV strain Edmonston, respectively. It was also found that compound 28a delivers good stability in human liver S9 fractions with a half-life of 165 minutes. These data establish 28a as a promising lead for antiviral therapy through a host-directed mechanism.