Cell Entry Inhibitors for Sin Nombre Virus

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DESCRIPTION (provided by applicant): Many of the pathogens that have properties that would be desirable to a would-be bioterrorist have been little-studied, in part because they cause a relatively limited toll in morbidity and mortality under natural circumstances. In other cases, such as for the North American hantaviruses, poor and medically underserved minority populations are disproportionately affected, making their toll even less visible. Two minority institutions in New Mexico, the University of New Mexico and New Mexico State University, have nevertheless devoted much attention to research on potential weapons of mass destruction (Sin Nombre virus or SNV, anthrax, tularemia, plague, etc) for years, with funding from at least four federal agencies. The hantavirus research portfolio at UNM, for example, has been funded at least $1 million direct/year essentially since its inception in 1994. The anthrax attacks of 2001 demonstrated the willingness and ability of terrorists to deploy bioweapons, which caused panic and severe economic damage. Countermeasures against WMD must be developed quickly to limit the damage exacted by future attacks. This application represents a concerted attack against SNV, a hantavirus that has killed over 100 Americans, including 26 New Mexicans, since its recognition in 1993. We have assembled an interdisciplinary team that pools its resources and skills in novel ways. We have developed interlocking, highly collaborative and cross-informing projects and cores involving project PIs who are genuine leaders in their fields, including several who have worked together productively in the past. The approaches that we have taken in this application will serve as a model that can be adapted successfully to a variety of pathogens other than hantaviruses. By pioneering new collaborative strategies using the SNV model, we will establish efficient, high-throughput methods that will work well against other agents. The core capabilities we describe herein will include high-throughput screening for antiviral effects of drugs, computer-assisted modeling that will be used to quickly refine and optimize lead compounds, and evaluation of the efficacy of drugs with sophisticated and quantitative animal model testing. The projects include (1) phage display to develop lead compounds that inhibit SNV entry into cells; (2) computational modeling of drugs; (3) development of RNA aptamer inhibitors of replication and/or packaging using SELEX; (4) development of potent human anti-SNV monoclonal antibodies; and (5) development of sophisticated mechanism-of-action assays to speed development of replicative inhibitors of SNV. Animal model, virology and structural analyses cores will each provide multiple projects with critical reagents or perform the molecular modeling services that are needed to improve lead compounds.