Importance of envelope protein glycosylation for the morphogenesis of Flaviviridae and its inhibition by new generation antivirals

Several viruses of the Flaviviridae family are causing agents of human pathologies, including haemorrhagic fever (e.g. Dengue virus, Yellow fever virus), encephalitis (e.g. Japanese encephalitis virus), or chronic hepatitis (Hepatitis C virus). For most of these diseases, while no vaccine have been developed to date, either no or non optimal treatments are currently available. New antivirals are needed to better combat Flaviviridae induced diseases. Molecules targeting specifically viral enzymes are the most attractive in terms of drug development and are therefore the most studied. However, an antiviral strategy based uniquely on the utilisation of this type of molecules is expected to encounter problems caused by the emergence of viral escape mutants, as already widely described for HIV and HBV. Alternative approaches would include targeting either a viral function that is less likely to give rise to viral escape mutants, or a host cell encoded function that would be crucial for the virus, but not for the cell itself. The viral assembly and morphogenesis belong to these new potential targets yet not exploited. Recently inhibitors of morphogenesis have been identified and studied in different virus/cell systems. Some of them are currently evaluated in clinical trials against HCV. The present review focuses on the Flaviviridae morphogenesis and its inhibition; and presents clinical development perspectives of this new generation of antivirals.