The possibility of biological terrorism has moved from the realm of speculation into reality. This threat can take several forms. One of the most likely pathogens in such a scenario is smallpox. The same characteristics that made smallpox a dreaded human pathogen, including aerosol infectivity and stability outside a human host, make it a potentially devastating biological weapon. Dissemination of smallpox in a major population center could result in the sudden, simultaneous occurrence of thousands of cases of severe illness. The primary reason for this is that so few people are now protected from infection by prior vaccination as a consequence of the declaration in 1980 of the complete eradication of smallpox. Furthermore, vaccination would be of little benefit to persons already infected by terrorist release of the virus and immediate vaccination of the exposed population might not reduce the infectivity of primary cases to prevent secondary transmission. Vaccine availability and quality would also prevent a massive vaccination effort. Because of these limitations, development of chemotherapeutic agents to combat smallpox infection must be undertaken. No such agents currently exist. To address this need, this proposal presents plans for developing drugs that act by inhibiting the enzymes encoded by the smallpox virus upon infection. Focus will be on nucleosides and nucleotides that effect, primarily, nucleic acid metabolism. A consortium of three chemists and two virologists as project leaders, and a virologist consultant, has been put into place for this purpose.