Vaccinia Virus Inhibitors as a Paradigm for the Chemotherapy of Poxvirus Infections

INTRODUCTION It has been more than 22 years since the last case of smallpox was confirmed and 20 years since the World Health Organization declared that the global eradication of smallpox had been achieved. The subsequent discontinuation of vaccination against smallpox (with vaccinia virus [VV] vaccine) has rendered most humans vulnerable to smallpox infection. The recent outbreak of monkeypox (against which the smallpox vaccine is protective) in the Democratic Republic of the Congo (formerly Zaire) and the genuine threat that variola virus, the etiological agent of smallpox, might be used as a biological weapon in warfare or terrorism (14, 60) have instigated the search for control measures to prevent or treat smallpox, mon-keypox, and poxvirus infections in general. Fittingly, the search for antiviral agents started with the poxviruses as target, when, over 50 years ago, the thiosemicar-bazones, introduced by Domagk et al. (53) as tuberculostatic (antituberculous) agents, were also found to be active against VV (57). This work was continued by Bauer (5) and culminated in the demonstration by Bauer et al. (8) in 1963 that the thiosemicarbazone derivative methisazone (Marboran, N-methylisatin 3-thiosemicarbazone) was effective in the prophy-laxis of smallpox. In several trials during Indian epidemics, methisazone proved its value by reducing the attack rate by 75 to 95%. Promising results have also been reported in the treatment of the complications of smallpox vaccination, vaccinia gangrenosa and eczema vaccinatum (55). As the principal side