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Nat Biotechnol. 2017 Jun 12. doi: 10.1038/nbt.3907. [Epub ahead of print]
Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site.
Strauch EM1,2, Bernard SM3, La D1, Bohn AJ4, Lee PS3, Anderson CE5, Nieusma T3, Holstein CA5, Garcia NK6, Hooper KA7, Ravichandran R2, Nelson JW1, Sheffler W1, Bloom JD7, Lee KK6, Ward AB3, Yager P5, Fuller DH4,8, Wilson IA3, Baker D1,2,9.
Author information
Abstract
Many viral surface glycoproteins and cell surface receptors are homo-oligomers, 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 sites. 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.
PMID: 28604661 DOI: 10.1038/nbt.3907
Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site.
Strauch EM1,2, Bernard SM3, La D1, Bohn AJ4, Lee PS3, Anderson CE5, Nieusma T3, Holstein CA5, Garcia NK6, Hooper KA7, Ravichandran R2, Nelson JW1, Sheffler W1, Bloom JD7, Lee KK6, Ward AB3, Yager P5, Fuller DH4,8, Wilson IA3, Baker D1,2,9.
Author information
Abstract
Many viral surface glycoproteins and cell surface receptors are homo-oligomers, 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 sites. 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.
PMID: 28604661 DOI: 10.1038/nbt.3907