Journal
NATURE BIOTECHNOLOGY
Volume 35, Issue 7, Pages 667-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3907
Keywords
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Categories
Funding
- DTRA [HDTRA1-16-C-0029, HDTRA1-11-1-0041]
- Life Science Discovery Fund [9598385]
- NIH [5R01AI096184-05, R01 GM102198]
- NIH/NIAID [R21AI119258]
- NW regional center of excellence (NIAID)
- NRSA [T32GM007270]
- Skaggs Institute for Chemical Biology at TSRI
- National Science Foundation [DGE-1256082]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- [R56 AI117675]
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Many viral surface glycoproteins and cell surface receptors are homo-oligomers(1-4), 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 homooligomeric target sites(5-8). 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.
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