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Department of Energy Office of Science
GM/CA @ APS Sponsors:
National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)

Designing antibodies to Influenza

Ian Wilson group (The Scripps Research Institute) and collaborators


Protein-protein interactions are the foundation of many biological processes from immune recognition and adhesion to signaling and cell motility, and disruption of these interactions can have profound consequences for protein function and impact human disease. However, understanding of the physicochemical basis of the affinity and specificity of protein-protein interactions is very limited. The ability to reprogram protein-protein interfaces or design new interactions de novo would be a great advance, and would enable the design of synthetic antibodies and other binding proteins for the treatment of diseases, such as cancer and influenza. To this end, the groups of Ian Wilson and David Baker (University of Washington) sought to develop computational methods for the design of novel binding proteins de novo. Using these methods, they created two synthetic proteins targeting the influenza-virus hemagglutinin at a site recognized by the broadly-neutralizing antibody CR6261. These proteins, HB36 and HB80, bind hemagglutinin with high affinity, exhibit cross-reactive binding to multiple virus subtypes resembling that of CR6261, and HB80 is able to block critical conformational changes in the hemagglutinin protein that are required for virus entry. The molecular precision of the design was confirmed by X-ray crystallography, using a GM/CA @ APS beamline. While further work is needed to characterize the activity of HB36 and HB80 and explore their possible use in a therapeutic setting, this work has demonstrated the feasibility of using de novo protein design for the creation of novel antiviral proteins, and may facilitate the future design of diagnostic and therapeutic proteins for the treatment of human disease.

Figure: The complex between designed protein, HB36 (red) and hemagglutinin (yellow, green, and blue).


Citation: Fleishman SJ, Whitehead TA, Ekiert DC, Dreyfus C, Corn JE, Strauch E-M, Wilson IA, Baker D. Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin. Science. 2011 May 13; 332: 816-21. doi: 10.1126/science.1202617.

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