tetano
Editor, Senior Moderator
Nat Biotechnol. 2017 Jun 12. doi: 10.1038/nbt.3907. [Epub ahead of print]
[h=1]Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site.[/h] Strauch EM[SUP]1,[/SUP][SUP]2[/SUP], Bernard SM[SUP]3[/SUP], La D[SUP]1[/SUP], Bohn AJ[SUP]4[/SUP], Lee PS[SUP]3[/SUP], Anderson CE[SUP]5[/SUP], Nieusma T[SUP]3[/SUP], Holstein CA[SUP]5[/SUP], Garcia NK[SUP]6[/SUP], Hooper KA[SUP]7[/SUP], Ravichandran R[SUP]2[/SUP], Nelson JW[SUP]1[/SUP], Sheffler W[SUP]1[/SUP], Bloom JD[SUP]7[/SUP], Lee KK[SUP]6[/SUP], Ward AB[SUP]3[/SUP], Yager P[SUP]5[/SUP], Fuller DH[SUP]4,[/SUP][SUP]8[/SUP], Wilson IA[SUP]3[/SUP], Baker D[SUP]1,[/SUP][SUP]2,[/SUP][SUP]9[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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
[h=1]Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site.[/h] Strauch EM[SUP]1,[/SUP][SUP]2[/SUP], Bernard SM[SUP]3[/SUP], La D[SUP]1[/SUP], Bohn AJ[SUP]4[/SUP], Lee PS[SUP]3[/SUP], Anderson CE[SUP]5[/SUP], Nieusma T[SUP]3[/SUP], Holstein CA[SUP]5[/SUP], Garcia NK[SUP]6[/SUP], Hooper KA[SUP]7[/SUP], Ravichandran R[SUP]2[/SUP], Nelson JW[SUP]1[/SUP], Sheffler W[SUP]1[/SUP], Bloom JD[SUP]7[/SUP], Lee KK[SUP]6[/SUP], Ward AB[SUP]3[/SUP], Yager P[SUP]5[/SUP], Fuller DH[SUP]4,[/SUP][SUP]8[/SUP], Wilson IA[SUP]3[/SUP], Baker D[SUP]1,[/SUP][SUP]2,[/SUP][SUP]9[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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