In a bioterror attack, as in a natural outbreak of an infectious disease, cases can appear very quickly and incapacitate the health care system. The CDC has ranked viral hemorrhagic fevers (VHF) among the highest of the potential bioterror threats, in part because of their high case-fatality ratio, their relatively high infectiousness, and the general lack of effective or specific therapies (www.bt.cdc.gov/Agent/Agentlist.asp). Because VHF are almost all rare, at least in the West, there has been little impetus to develop and license new therapies or vaccines, so the health care system is virtually inelastic in its ability to accommodate a marked increase in cases such as might occur through a bioterror attack. The very rarity of VHF makes it extremely unlikely that private industry will have sufficient motivation to develop anti-VHF treatments for the sake of profit. We see a critical need for a generic strategy to rapidly develop specific antivirals for known agents, a technology that will serve a dual purpose. The first purpose is to produce a library of lead antiviral compounds that can be moved as needed through a development pipeline toward practical small-molecule antiviral agents. The second purpose is to develop a high- throughput, robust, practical strategy that would enable investigators to reliably and quickly develop lead compounds against new agents, or agents that have been genetically manipulated by bioterrorists. We have chosen phage display technology as a platform that puts immense drug selection power in the hands of groups with modest resources, such as academic investigators. As a model VHF we have chosen Sin Nombre virus (SNV), a hantavirus member of the Group A list of candidate organisms of bioterror; a virus that causes a VHF with high mortality that is indigenous to the United States and for which current treatment is unsatisfactory. Our group has both considerable direct experiences with SNV as well as relevant preliminary data that suggest that a direct antiviral inhibitor would probably be effective in reducing mortality. Our goal is to (1) identify small molecule inhibitors that bind to and neutralize SNV, and (2) develop new technologies that will improve the ease of discovery and pace of discovery of small molecule inhibitors of other threat agents.
