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Mechanism of Action for Drugs Against Arenaviruses

The U.S. Army Medical Research Acquisition Activity (USAMRAA) is seeking firms capable of providing research services to develop mechanisms of action for FDA-approved drugs against Arenaviruses.

The contract will support ongoing work on biothreat countermeasures by the Virology Division within the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).

USAMRIID has screened a library containing over 3200 FDA-approved drugs to identify ones that inhibit infections by multiple pathogenic viruses. Those tested include six hemorrhagic fever viruses (Ebolavirus, Marburgvirus, Dengue Virus, West Nile Virus, Lassa Fever Virus, and Rift Valley Fever Virus) and four alphaviruses (Western, Eastern, and Venezuelan encephalitis viruses and Chikungunya virus), representing 5 families of enveloped RNA viruses (filo-, flavi-, arena-, bunya-, and alphaviruses).

From this effort, they have identified approximately 140 Highly Active Anti-viral Lead Therapeutics (HALLT) compounds that block infection by members of two or more virus families. Understanding the Mechanism of Action (MOA) would improve understanding as to how these compounds may be inhibiting infection and at which stage of virus replication to develop more effective therapeutics.

Previous efforts against filoviruses have focused on specifically designed Ebolavirus (EBOV) virus like particles (VLPs) that recapitulate the filamentous shape and entry properties of authentic EBOV, through the incorporation of the EBOV glycoprotein (GP). Just like other enveloped viruses, it is the GP that dictates all aspects of virus entry. Additionally, these VLPs incorporate two engineered forms of EBOV VP40, one tagged with β-lactamase and one tagged with mCherry. VP40 directs the assembly of EBOV VLPs, similar to authentic virus. The β-lactamase VP40 acts a reported when the VLPs have fused with a cellular membrane and have entered into the cytoplasma; whereas, the mCherry VP40 provides a fluorescent tag for visualizing the VLPs during cellular entry.

The proposed work for this solicitation is to develop a similar pseudoviron assay for arenaviruses and identify the mechanism of action of several compounds identified in the authentic virus screens completed by USAMRIID.

USAMRAA anticipates awarding a single contract for one base year plus four option years for these services.

Further details are available under Solicitation Number: W81XWH-14-R-0082. The response deadline is July 31, 2014.

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