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Designed Protein Overcomes Epstein-Barr Virus Strategy Of Evading Immune System

by on June 27, 2014
 

Researchers have for the first time using powerful computers and algorithms designed a completely novel protein that kills virally infected cells, including ones which are associated with certain kinds of cancers.

Proteins are the internal machines of cells that have particular molecular shapes and carry out functions specific for each shape.  The designed protein is called BINDI, which stands for BHRF1-INhibiting Design acting Intracellularly.  BINDI was made to target cells that carry Epstein-Barr virus (EBV).  The novel protein binds the virus in the “picomolar” range, or about 1000 times more tightly than most drugs on the market.

There is precedence for designing superstable proteins though most of these lacked biological function.  And there is precedence for designing new functions within existing scaffolds of proteins.  However thus far there have been no examples of both designed new structure and function simultaneously, which is the great advance in this work.

In general, computational design of bioactive molecules is a difficult task, and in fact the 2013 Nobel Prize in chemistry was awarded to Martin Karplus and Michael Levitt for work in the very related field of computational molecular dynamics.

Designed protein BINDI (red) inactivating essential viral protein BHFR1 (gray).

Designed protein BINDI (red) inactivating essential viral protein BHFR1 (gray).

The researchers chose EBV because it is significant due to its high prevalence of 90% in the population though it is largely dormant.  While usually virally-infected cells get targeted for destruction by the immune system, EBV is able to evade the immune system due to a special molecule that acts like a “brake” preventing infected cells from being destroyed. The BINDI molecule was designed to bind to the “brake” molecule and inactivate it, thus allowing infected cells to be targeted for destruction.

EBV is also associated with lymphomas, or a cancer of white blood cells originating from the lymph nodes.  The research, carried out by researcher Dr. Erik Procko and headed by Professor David Baker of the University of Washington, showed that the BINDI molecule exerted powerful therapeutic effects against EBV-driven lymphomas induced in mice by extending survival by 50%.

David Baker’s lab at the University of Washington is also responsible for the breakthrough software Rosetta which is renowned worldwide for its accuracy in predicting protein folds and designing protein-protein interactions.

http://www.cell.com/abstract/S0092-8674(14)00613-8

(Photo Credits: Dr. Erik Procko)

 

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