Viral coat protein arrays for rapid development and screening of anti-fusogenic antivirals against Ebolavirus

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The Ebola virus infection begins when viruses enter specific cells in the body, through a process involving binding to the cell surface followed by fusion during which the virus releases its genetic material into the cell. If either binding or fusion is interrupted, the virus will no longer be able to cause infection. The main objective of this work is to develop therapeutics that block virus fusion to the cell. To accomplish this, the PI will use a novel in vitro platform that allows her to screen for virus fusion preventing compounds. At the conclusion of this work, the benefit to society will be: 1) a screening tool that can be readily adapted to discover compounds to combat future viral outbreaks, and 2) antibody candidates that can be used to stop the progression of the current Ebola virus disease outbreak. Additionally, the investigators will interact with the public to provide information about the Ebola virus, its infection process, and factors that contribute to outbreaks such as the current one.Technical Abstract: At present, there are no available screening tools that can directly test the efficacy of anti-fusogenic compounds against Ebola. The fusion step is an especially promising target for therapeutics, as the fusion domain of Ebola virus spike protein (GP) evolves much slower than its binding domain. To address the urgent national need to identify compounds that stop Ebola virus infection, the PI proposes to (1) create a rapid screening platform for anti-fusogenic compounds against Ebola virus; and (2) identify antibodies and compounds that disrupt the fusion function of GP. The PI will adapt a microfluidic virus fusion assay platform based on her previous work using single particle tracking (SPT) approaches to investigate enveloped virus fusion. The platform consists of a multi-channel microfluidic device with host cell mimics coated on the channel walls (referred to as a supported lipid bilayer, SLB), and virus (or virus-like particles, VLPs) containing Ebola virus GP protein that can fuse with the SLB. This technology directly probes viral fusion in a high-throughput manner and provides quantitative information on the fusion mechanism. It is anticipated that this platform can be used for the rapid screening and identification of anti-fusogenic antiviral compounds against Ebola virus. In addition, the PIs will participate in public discourse about the virus, providing information about the infection process and providing perspective about the outbreak through such activities as presentations to the medical staff at the regional hospital (Cayuga Medical Center) as part of their Continuing Education Series and Ebola-response plan.