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Title: Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site

Abstract

Many viral surface glycoproteins and cell surface receptors are homo-oligomers1, 2, 3, 4, and thus can potentially be targeted by geometrically matched homo-oligomers that engage all subunits simultaneously to attain high avidity and/or lock subunits together. The adaptive immune system cannot generally employ this strategy since the individual antibody binding sites are not arranged with appropriate geometry to simultaneously engage multiple sites in a single target homo-oligomer. We describe a general strategy for the computational design of homo-oligomeric protein assemblies with binding functionality precisely matched to homo-oligomeric target sites5, 6, 7, 8. In the first step, a small protein is designed that binds a single site on the target. In the second step, the designed protein is assembled into a homo-oligomer such that the designed binding sites are aligned with the target sites. We use this approach to design high-avidity trimeric proteins that bind influenza A hemagglutinin (HA) at its conserved receptor binding site. The designed trimers can both capture and detect HA in a paper-based diagnostic format, neutralizes influenza in cell culture, and completely protects mice when given as a single dose 24 h before or after challenge with influenza.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER
OSTI Identifier:
1375353
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Biotechnology; Journal Volume: 35; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Strauch, Eva-Maria, Bernard, Steffen M., La, David, Bohn, Alan J., Lee, Peter S., Anderson, Caitlin E., Nieusma, Travis, Holstein, Carly A., Garcia, Natalie K., Hooper, Kathryn A., Ravichandran, Rashmi, Nelson, Jorgen W., Sheffler, William, Bloom, Jesse D., Lee, Kelly K., Ward, Andrew B., Yager, Paul, Fuller, Deborah H., Wilson, Ian A., and Baker, David. Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site. United States: N. p., 2017. Web. doi:10.1038/nbt.3907.
Strauch, Eva-Maria, Bernard, Steffen M., La, David, Bohn, Alan J., Lee, Peter S., Anderson, Caitlin E., Nieusma, Travis, Holstein, Carly A., Garcia, Natalie K., Hooper, Kathryn A., Ravichandran, Rashmi, Nelson, Jorgen W., Sheffler, William, Bloom, Jesse D., Lee, Kelly K., Ward, Andrew B., Yager, Paul, Fuller, Deborah H., Wilson, Ian A., & Baker, David. Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site. United States. doi:10.1038/nbt.3907.
Strauch, Eva-Maria, Bernard, Steffen M., La, David, Bohn, Alan J., Lee, Peter S., Anderson, Caitlin E., Nieusma, Travis, Holstein, Carly A., Garcia, Natalie K., Hooper, Kathryn A., Ravichandran, Rashmi, Nelson, Jorgen W., Sheffler, William, Bloom, Jesse D., Lee, Kelly K., Ward, Andrew B., Yager, Paul, Fuller, Deborah H., Wilson, Ian A., and Baker, David. Mon . "Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site". United States. doi:10.1038/nbt.3907.
@article{osti_1375353,
title = {Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site},
author = {Strauch, Eva-Maria and Bernard, Steffen M. and La, David and Bohn, Alan J. and Lee, Peter S. and Anderson, Caitlin E. and Nieusma, Travis and Holstein, Carly A. and Garcia, Natalie K. and Hooper, Kathryn A. and Ravichandran, Rashmi and Nelson, Jorgen W. and Sheffler, William and Bloom, Jesse D. and Lee, Kelly K. and Ward, Andrew B. and Yager, Paul and Fuller, Deborah H. and Wilson, Ian A. and Baker, David},
abstractNote = {Many viral surface glycoproteins and cell surface receptors are homo-oligomers1, 2, 3, 4, and thus can potentially be targeted by geometrically matched homo-oligomers that engage all subunits simultaneously to attain high avidity and/or lock subunits together. The adaptive immune system cannot generally employ this strategy since the individual antibody binding sites are not arranged with appropriate geometry to simultaneously engage multiple sites in a single target homo-oligomer. We describe a general strategy for the computational design of homo-oligomeric protein assemblies with binding functionality precisely matched to homo-oligomeric target sites5, 6, 7, 8. In the first step, a small protein is designed that binds a single site on the target. In the second step, the designed protein is assembled into a homo-oligomer such that the designed binding sites are aligned with the target sites. We use this approach to design high-avidity trimeric proteins that bind influenza A hemagglutinin (HA) at its conserved receptor binding site. The designed trimers can both capture and detect HA in a paper-based diagnostic format, neutralizes influenza in cell culture, and completely protects mice when given as a single dose 24 h before or after challenge with influenza.},
doi = {10.1038/nbt.3907},
journal = {Nature Biotechnology},
number = 7,
volume = 35,
place = {United States},
year = {Mon Jun 12 00:00:00 EDT 2017},
month = {Mon Jun 12 00:00:00 EDT 2017}
}