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The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target.

ABSTRACT: The highly virulent nature of Ebola virus, evident from the 2014 West African pandemic, highlights the need to develop vaccines or therapeutic agents that limit the pathogenesis and spread of this virus. While vaccines represent an obvious approach, targeting virus interactions with host proteins that critically regulate the virus lifecycle also represent important therapeutic strategies. Among Ebola virus proteins at this critical interface is its matrix protein, VP40, which is abundantly expressed during infection and plays a number of critical roles in the viral lifecycle. In addition to regulating viral transcription, VP40 coordinates virion assembly and budding from infected cells. Details of the molecular mechanisms underpinning these essential functions are currently being elucidated, with a particular emphasis on its interactions with host proteins that control virion assembly and egress. This review focuses on the strategies geared toward developing novel therapeutic agents that target VP40-specific control of host functions critical to virion transcription, assembly and egress.

SUBMITTER: Madara JJ

PROVIDER: S-EPMC4480923 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target.

Madara Jonathan J JJ Han Ziying Z Ruthel Gordon G Freedman Bruce D BD Harty Ronald N RN

Future virology 20150501 5

The highly virulent nature of Ebola virus, evident from the 2014 West African pandemic, highlights the need to develop vaccines or therapeutic agents that limit the pathogenesis and spread of this virus. While vaccines represent an obvious approach, targeting virus interactions with host proteins that critically regulate the virus lifecycle also represent important therapeutic strategies. Among Ebola virus proteins at this critical interface is its matrix protein, VP40, which is abundantly expre ...[more]

PMID: 26120351

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Project description:The Ebola virus (EBOV) is a lipid-enveloped virus with a negative sense RNA genome that can cause severe and often fatal viral hemorrhagic fever. The assembly and budding of EBOV is regulated by the matrix protein, VP40, which is a peripheral protein that associates with anionic lipids at the inner leaflet of the plasma membrane. VP40 is sufficient to form virus-like particles (VLPs) from cells, which are nearly indistinguishable from authentic virions. Due to the restrictions of studying EBOV in BSL-4 facilities, VP40 has served as a surrogate in cellular studies to examine the EBOV assembly and budding process from the host cell plasma membrane. VP40 is a dimer where inhibition of dimer formation halts budding and formation of new VLPs as well as VP40 localization to the plasma membrane inner leaflet. To better understand VP40 dimer stability and critical amino acids to VP40 dimer formation, we integrated computational approaches with experimental validation. Site saturation/alanine scanning calculation, combined with molecular mechanics-based generalized Born with Poisson-Boltzmann surface area (MM-GB/PBSA) method and molecular dynamics simulations were used to predict the energetic contribution of amino acids to VP40 dimer stability and the hydrogen bonding network across the dimer interface. These studies revealed several previously unknown interactions and critical residues predicted to impact VP40 dimer formation. In vitro and cellular studies were then pursued for a subset of VP40 mutations demonstrating reduction in dimer formation (in vitro) or plasma membrane localization (in cells). Together, the computational and experimental approaches revealed critical residues for VP40 dimer stability in an alpha-helical interface (between residues 106-117) as well as in a loop region (between residues 52-61) below this alpha-helical region. This study sheds light on the structural origins of VP40 dimer formation and may inform the design of a small molecule that can disrupt VP40 dimer stability.

Dataset Information

The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target.

Publications

The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target.

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