Most
antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell
proteins that are utilized by viruses during
infection. The small molecule
WP1130 is a selective
deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of
WP1130 to identify compounds that retained the broad-spectrum
antiviral activity of the parent compound in vitro but exhibited improved
drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine
norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than
WP1130 (1.9 to 2.6 log scale).
Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus
RNA. No significant cytotoxicity was observed at the working concentration of 5 µM for all compounds tested. In addition, the
WP1130 derivatives maintained their broad-spectrum
antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of
WP1130 can maintain effective broad-spectrum
antiviral activity while increasing aqueous solubility.