Henipaviruses show increasing impact as causes of central nervous system illness in the human community. We propose to apply our understanding of paramyxovirus entry to the development of new strategies for inhibiting infection that will apply to newly emerging paramyxoviruses. The first step in paramyxovirus infection is the binding of the receptor-binding protein (G for Hendra and Nipah viruses; HeV/NiV) to receptor on the cell's surface (EFNB2 for HeV/NiV). Receptor engagement activates the viral fusion proteins (F) to fusion-ready conformation, and F then inserts into the target cell membrane, fusing the viral envelope with the cell's membrane and allowing viral entry. In a novel therapeutic approach, we will identify compounds that induce F to trigger prematurely, inactivating the viruses before they can enter the target cells. 1. Proof of concept for new antiviral platform: Paramyxovirus receptor mimics induce premature triggering of F distant from the target cell.
This aim will test the hypothesis that if G-receptor interaction can be mimicked before an infectious viral particle binds to the cell surface, F can be induced to be triggered prematurely and be inactivated. We will assess whether soluble receptor-mimicking molecules inhibit multicycle replication in relevant tissue models for human vascular endothelium and for human CMS parenchymal cells. Support of this aim includes evidence for
Hendra and Nipah viruses are urgent concerns for public health due to their transmissible nature and increasing impact on acute and chronic central nervous system disease. This research proposal will lead to a new antiviral strategy that will apply to henipaviruses, existing and emerging paramyxoviruses as well as other enveloped viruses. The results will be highly relevant in light of the importance of paramyxoviruses to human health and the potential broad applicability of the new platform to these and other serious pathogens.
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