Selective inhibitors of the replication of poxviruses

Abstract

In case of an inadvertent epidemic with the smallpox virus that could not immediately (or not only) be controlled by vaccination, it will be of utmost importance to have effective antiviral drugs at hand for treatment and/or shortterm prophylaxis. Most advanced as a therapeutic or early prophylactic modality is cidofovir, a compound that has been licensed (as Vistide®) for the intravenous treatment of CMV retinitis in AIDS patients. Cidofovir is active in vitro against all (ortho)poxviruses studied so far; is effective in various relevant animal models, including cynomolgus monkeys infected with the monkeypox virus, and has shown efficacy in the clinical setting for the treatment of infections with molluscum contagiosum and orf. Cidofovir should also allow to treat severe complications of vaccination, as may occur in immunodeficient patients. Recently a selective non-nucleoside inhibitor of orthopoxvirus replication (ST-246) was reported that targets a major envelope protein that is involved in viral maturation and the production of infectious extracellular virus. ST-246 exhibits potent activity in mouse models of poxvirus infection. Also, the Abl-family tyrosine kinases and the ErbB-1 kinase were shown to play a crucial role in the replication cycle of poxviruses. Hence inhibitors of these kinases, turned out to be selective inhibitors of poxvirus replication, both in cell culture and in experimentally infected animals.