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Targeting the processing of arenavirus glycoprotein for anti-viral therapy

English title Targeting the processing of arenavirus glycoprotein for anti-viral therapy
Applicant Kunz Stefan
Number 120250
Funding scheme Project funding
Research institution Institut de Microbiologie - CHUV Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.04.2008 - 31.03.2011
Approved amount 396'838.00
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Keywords (8)

Arenavirus; hemorrhagic fever; glycoprotein; protease; emerging disease; developing world; anti-viral; processing

Lay Summary (English)

Lead
Lay summary
Viral hemorrhagic fevers caused by arenaviruses belong to the most devastating emerging viral diseases. These pathogens cause considerable human suffering in endemic areas in the developing world, and are regularly imported into metropolitan areas around the globe by air traffic. Lassa virus is endemic in Africa and causes over 300, 000 infections and thousands of deaths annually, representing a severe threat for human health and a major humanitarian problem. The arenaviruses Junin, Machupo, and Guanarito have emerged as etiological agents of severe hemorrhagic fevers in Latin America. Arenavirus hemorrhagic fevers have fatality rates of 15 to 35% with a limited antiviral therapeutic and vaccine repertoire available. Our project aims at the development of novel anti-viral strategies against these severe human pathogens. Out approach targets one of the crucial steps in the life cycle of arenaviruses, namely the biosynthesis of the viral envelope glycoprotein (GP) that is essential for virus-host cell attachment and entry. As obligatory cellular parasites arenaviruses largely rely on the biosynthetic machinery of the host cell for the production of viral proteins. During biosynthesis of the arenavirus GP, a GP precursor protein is processed by the cellular site 1 protease (S1P), a serine protease of the convertase family, to yield the mature functional viral envelope GP. Processing of arenavirus GP by S1P is crucial for infectious virus production and cell-to-cell propagation of the virus, making the proteolytic processing of the viral GP a promising target for therapeutic intervention. In the basic research aim of our proposal, we will perform a characterization of the molecular interaction between the GPs of highly pathogenic arenaviruses and S1P protease and investigate implications of the GP-S1P interaction for virus replication and viral disease. A second, translational research aim focuses on the discovery of specific small molecule inhibitors of the S1P-mediated processing of arenavirus GPs by high-throughput screening of collections of synthetic compounds. Initial hits from our screening will be subjected to counter-screening to identify candidate compounds that specifically inhibit processing of the viral GPs, but do not interfere with S1P’s function in the host cell. Candidate compounds will be tested for their ability to efficiently block infectious virus production and cell-to-cell propagation in human cells. The use of antiviral drugs is complicated by the frequent emergence of resistant virus variants. We will address the emergence of drug-resistant viral variants and analyze the sequences of their GPs to identify structural changes associated with drug resistance that may give valuable hints on the molecular mechanism of action of our drugs. Our approach to identify small molecule inhibitors of the processing of the arenavirus GP represents a perfect match between the powerful new technology of small molecule screening with an unmet biological problem that may pave the way for the development of new therapeutics to combat highly pathogenic arenaviruses.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
132844 Host cell invasion by Lassa virus 01.01.2011 Project funding
143754 Immunoengineering a synthetic vaccine against emerging human pathogenic viruses 01.10.2012 Interdisciplinary projects
135536 Targeting the processing of arenavirus glycoprotein for anti-viral therapy 01.04.2011 Project funding

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