Viral hemorrhagic fevers (VHFs) are severe illnesses characterized by fever, multiple organ involvement and extensive vascular damage. Hemorrhagic fever viruses (HFVs), in particular Lassa fever (Arenaviridae), Rift Valley fever (Bunyaviridae), and Ebola and Marburg (Filoviridae) viruses are potential biological weapons agents due to their ease of dissemination, person-to-person transmissibility and potential to cause widespread illness and death. These HFVs are classified as Category A bioweapons agents by the Centers for Disease Control and Prevention (CDC). Currently, there are no licensed vaccines or FDA-approved antiviral drugs to prevent or treat VHF. The overall goal of our Category A Virus Biodefense Program is to discover and develop small molecule drugs for HFVs. The specific aims of this Phase 1 application are to: 1. Establish several validated virus-specific high throughput screening assays involving closely related surrogate, BSL-2 viruses or assay systems for arenaviruses, bunyaviruses and filoviruses; 2. Identify inhibitors specific for the targeted viruses from the VIROPHARMA proprietary, chemically diverse library of over 400,000 small molecule compounds using these virus-specific assays; 3. Characterize inhibitor compounds (hits) for chemical tractability, antiviral potency and selectivity, and spectrum of antiviral activity in order to identify promising "quality hits"; 4. Confirm antiviral specificity and selectivity of quality hits against the authentic targeted Category A viruses in cell culture (performed through collaborating laboratories); and 5. Initiate drug metabolism, genotoxicity & pharmacokinetic evaluations on confirmed quality hits. The end result of Phase 1 work will be identification of quality hits specific for at least two targeted viral agents. Advancement of these compounds in Phase 2 will involve: (1) hit-to-lead medicinal chemistry to identify leads with good potential for chemical structure-biological activity relationships (SAR); (2) lead compound optimization for antiviral potency, selectivity and spectrum of antiviral activity and drug metabolic and pharmacokinetics properties; (3) mechanism of action and drug resistance characterizations; and (4) safety and efficacy evaluations in suitable animal models.
Thesaurus Terms: Arenaviridae, Bunyaviridae, Mononegavirales, RNA virus, antiviral agent, drug design /synthesis /production, drug screening /evaluation, high throughput technology hemorrhagic fever, pharmacokinetics bioterrorism /chemical warfare, laboratory rat, tissue /cell culture
