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Review
. 2009 Mar;81(3):189-97.
doi: 10.1016/j.antiviral.2008.12.003. Epub 2008 Dec 27.

No exit: targeting the budding process to inhibit filovirus replication

Ronald N Harty  1
Affiliations
Review

No exit: targeting the budding process to inhibit filovirus replication

Ronald N Harty. Antiviral Res. 2009 Mar.

Abstract

The filoviruses, Ebola and Marburg, cause severe hemorrhagic fever in humans and nonhuman primates, with high mortality rates. Although the filovirus replication pathway is now understood in considerable detail, no antiviral drugs have yet been developed that directly inhibit steps in the replication cycle. One potential target is the filovirus VP40 matrix protein, the key viral protein that drives the budding process, in part by mediating specific virus-host interactions to facilitate the efficient release of virions from the infected cell. This review will summarize current knowledge of key structural and functional domains of VP40 believed to be necessary for efficient budding of virions and virus-like particles. A better understanding of the structure and function of these key regions of VP40 will be crucial, as they may represent novel and rational targets for inhibitors of filovirus egress.

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Figures

Figure 1
Figure 1
Electron micrographs of EBOV VP40 VLPs budding from the surface of human 293T cells. Ultrathin sections were examined with a Philips CM-100 transmission electron microscope equipped with a KeenView digital camera system.
Figure 2
Figure 2
Top - Diagram depicting a monomer of EBOV VP40 with the M, I, and L domains highlighted. The locations of the M and I domains are for illustrative purposes and have yet to be defined precisely. In the absence of inhibitors, the M domain will mediate membrane binding, the I domain will mediate homo-oligomerization, and the L-domains will mediate interactions with host proteins Tsg101 and Nedd4 leading to efficient budding of virions or VLPs. Bottom – The red Xs represent potential target sites for inhibitors of budding. Inhibitors of L-domain function would prevent VP40 interactions with Tsg101 or Nedd4, and inhibitors of vps4 would disrupt the ESCRT machinery to impair virus egress.
Figure 3
Figure 3
Protocol to identify candidate inhibitors of an EBOV VP40 PTAP-Tsg101 interaction.
See this image and copyright information in PMC

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