Flaviviruses pose a constant threat to emerge as epidemics or pandemics. For instance dengue virus (DENV), which can cause hemorrhagic fevers, is one of the world’s fastest growing infectious disease. We have recently identified a compound (C10) that shows excellent antiviral activity against members of the flaviviridae family hepatitis c virus (HCV), dengue DENV, WNV and Zika virus (ZIKV). C10 is moderately active against other RNA-viruses influenza A virus (H1N1), respiratory syncytial virus (RSV) and also the alphavirus chikungunya virus (CHIKV) but it is non-effective against measles virus (MeV), human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Furthermore, C10 is non-cytotoxic even at high concentrations over prolonged incubation periods. Since our initial screen focused on identifying compounds that bind to and interfere with the proper self-interaction of the HCV capsid protein core, we hypothesize that the broad activity of C10 against flaviviridae is based on a general mechanism that could be due to structural similarities within flaviviral capsids. Major goals are target validation by structural analyses and generation of resistant viruses. This knowledge will be used for rationale-based structure activity relationship (SAR) studies. Altogether, we will identify an optimized lead compound as a novel class of broadly acting antiviral against various flaviviruses.
Funded by BW Stiftung.
