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Broad-spectrum inhibitors of ebolavirus entry


EMSL Project ID
50942

Abstract

There are six known viruses in the ebolavirus genus, at least three of which are known to cause severe hemorrhagic fever in humans. All ebolaviruses display one surface protein, a glycoprotein termed GP, which is solely responsible for attachment to and entry into host cells. GP is the key target of inhibitors of virus entry and antibodies that target the virus. GP is up to 50% different in amino acid sequence across the ebolaviruses. As a result, vaccines and antibody therapeutics currently in clinical trials are effective against only one of these viruses, leaving us vulnerable to outbreaks of the others. Rare, broadly reactive anitbodies, and novel, broadly-reactive designed proteins have recently been identified with activity against multiple ebolaviruses. We will determine the specific protein-protein interaction surfaces engaged by two types of protein-based inhibitors to learn how they work, how they achieve their broad specificity, and how they can be improved. If successful, these structures will impact the ongoing development of broad-spectrum vaccines, diagnostics, and therapeutics. The specific objective is to use single-particle cryo-electron microscopy (cryo-EM) to obtain data to determine the structure of each of these molecules in complex with ebolavirus GP. The time we request at PNCC will be used to obtain hands-on training in grid preparation, data collection and data processing to optimize conditions for each protein complex. A major goal of this proposal is for the lead scientist (Emilia Arturo) to develop independence in the use of cryo-EM techniques to determine high resolution protein structures.

Project Details

Start Date
2019-06-15
End Date
2019-12-31
Status
Closed

Team

Principal Investigator

Erica Saphire
Institution
La Jolla Institute for Immunology

Team Members

Michelle Moss
Institution
La Jolla Institute for Immunology

Emilia Arturo
Institution
La Jolla Institute for Immunology

Harry Scott
Institution
Oregon Health & Science University