Synthesis and Metabolic Studies of Host Directed Inhibitors for Anti Viral Therapy

• Published in: ACS medicinal chemistry letters Vol. 4; no. 8; pp. 762 - 767
• Main Authors: Moore, Terry W, Sana, Kasinath, Yan, Dan, Krumm, Stefanie A, Thepchatri, Pahk, Snyder, James P, Marengo, José, Arrendale, Richard F, Prussia, Andrew J, Natchus, Michael G, Liotta, Dennis C, Plemper, Richard K, Sun, Aiming
• Format: Journal Article
• Language: English
• Published: United States 08.08.2013
• Subjects: benzimidazole; influenza A; Myxovirus inhibitor; host-directed; respiratory syncytial virus; metabolic stability
• ISSN: 1948-5875; 1948-5875

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 ( and ) 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, , with EC values of 0.88 and 0.81 μM against IAV strain WSN and MeV strain Edmonston, respectively. It was also found that compound delivers good stability in human liver S9 fractions with a half-life of 165 minutes. These data establish as a promising lead for antiviral therapy through a host-directed mechanism.