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Development of Small Molecule Therapeutics Specifically Targeting Members of the Bunyavirales Order


KEY TECHNOLOGY AREA(S): Chemical/Biological Defense, Biomedical OBJECTIVE: Develop an antiviral drug to be used as a therapeutic in the event of disease or as a prophylactic medical countermeasure (MCM) following exposure or threat of exposure to viruses of the Bunyavirales order. DESCRIPTION: The Bunyaviridae are a very large family of single-strand, enveloped RNA viruses (more than 300 viruses) and consists of five genera of viruses: Orthobunyavirus, Phlebovirus, Nairovirus, Hantavirus, and Tospovirus (Tospoviruses infect only plants). They are found in and transmitted by arthropods (e.g. mosquitoes, ticks, sand flies) and rodents, and can occasionally infect humans. Several viruses of the Bunyaviridae virus family can produce mild to severe disease in human, in animals, and sometimes in both.1 Hantaviruses were first observed in the early 1950’s among troops deployed in the Korean conflict. Eventually named Hantaan virus after the nearby Hantaan River where the human cases occurred, the field mouse (Apodemus agrarius) was discovered to be the specific rodent host for the virus. The disease is actually known as Hemorrhagic fever with renal syndrome (HFRS) and described in the Old World. Following a cluster of cases of severe illness, called Hantavirus Pulmonary Syndrome (HPS), in the American southwest in 1993, a newly identified virus, called the Sin Nombre virus, was isolated. Related viruses, but responsible for the same clinical disease, are described in the New World (North, Central and South America).1 Emerging Viruses posing a threat to the warfighter include members of the Bunyavirales order (e.g. Rift Valley Fever virus [RVFV], Severe Fever with Thrombocytopenia Syndrome virus [SFTSV], Crimean-Congo Hemorrhagic Fever virus [CCHFV]; Sin Nombre virus [SNV]). Outbreaks of several of these viruses have occurred during 2018 in global areas of U.S. military presence. The presence of vectors in new areas where these viruses are not currently endemic could lead to expansion of endemic areas or pose sporadic outbreak risks. For example, SFTSV is a new emerging Phlebovirus in China, Japan, and South Korea that causes hemorrhagic fever with mortality rates of up to 30%, and the tick vector for SFTSV recently has been isolated in the United States. Autochthonous infection has been demonstrated for CCHFV, a Nairovirus whose global distribution in over 30 countries is second to Dengue virus. For some viruses, animal models have not been fully developed; thus, use of transgenic mouse or hamster lines or immunosuppression may be required for initial, in vivo assessments. 2, 3, 4 This topic seeks to identify small molecule inhibitors of any phase of virus replication. The preferred therapeutic is a small molecule that exhibits broad activity across virus families. Ideally the therapeutic can be self-administered orally or at least by administration within a reasonably short time frame in clinical settings. PHASE I: Identify small molecule inhibitors of Bunyavirus replication. A) Identification and development of working stocks of appropriate strains of virus(es) for testing. Alternatively, surrogate assays (e.g. pseudotyped particles, replicase assays) in lower safety containment laboratories are sufficient for early screening. Modeling data for potential broad-spectrum inhibition of Bunyavirus replication can be used to support intermediate development at the Phase II stage. B) Using high throughput screening of existing or novel libraries, identify small molecule inhibitors to virus replication of one or more of the members of the Bunyavirales order. The screening should assess antiviral activity and cytotoxicity. Studies that include any animal use will not be permitted during Phase I; obtaining all necessary DoD Animal Care and Use Review Office (AUCRO) approvals before any animal use may commence requires significant time and will preclude completing the Phase I project beyond the allowed six-month Phase I Period of Performance. PHASE II: The objective of this phase is to assess the antiviral properties of a target small molecule for eventual IND filing. This will be accomplished by: A) Using compounds identified through high throughput screening, or for compounds in more advanced development stages, confirm the mechanism of action of optimized candidates; B) Develop clinical material for determining the PK/PD and ADME (absorption, distribution, metabolism, and excretion) of the compound and half maximal effective concentration(s) (EC50); C) In a single or series of pilot experiments, determine appropriate dose (using PK/PD modeling informed by successive experimental approaches) in an applicable animal model and assess toxicity and efficacy against one or more viruses. This stage will require development of working stocks of appropriate strains of virus(es) for testing (if not developed in Phase I), and performance within high containment laboratories. PHASE III: Preclinical development of down-selected candidates to support submission of an application for an Investigational New Drug (IND). Construction of a Development Plan through consultation with a sponsor and the Food and Drug Administration (FDA). Discussions and preparations would include identification of appropriate virus strains, animal models, and if applicable, clinical trial location and development. PHASE III DUAL USE APPLICATIONS: The viral agents listed in this SBIR topic lack treatment options, and any therapeutic derived from this research will be of significant use for both civilian and military populations at risk. REFERENCES: 1. 2. Matsuno K, Orba Y, Maede-White K, Scott D, Feldmann F, Liang M and Ebihara H (2017) Animal Models of Emerging Tick-Borne Phleboviruses: Determining Target Cells in a Lethal Model of SFTSV Infection. Front. Microbiol. 8:104. 3. Haddock E, Feldmann F, Hawman DW, Zivcec M, Hanley PW, Saturday G, Scott DP, Thomas T, Korva M, Avšič –Županc T, Safronetz D, & Feldmann H. (2018) A cynomolgus macaque model for Crimean–Congo haemorrhagic fever. Nature Microbiology 3:556–562 (2018). 4. Wonderlich ER, Caroline AL, McMillen CM, Walters AW, Reed DS, Barratt-Boyes SM, Hartman AL. 2018. Peripheral blood biomarkers of disease outcome in a monkey model of Rift Valley fever encephalitis. J Virol 92:e01662-17.
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