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.