Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing
Identifieur interne : 000A34 ( Main/Exploration ); précédent : 000A33; suivant : 000A35Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing
Auteurs : Timothy A. Whitehead [États-Unis] ; Aaron Chevalier [États-Unis] ; Yifan Song [États-Unis] ; Cyrille Dreyfus [États-Unis] ; Sarel J. Fleishman [États-Unis] ; Cecilia De Mattos [États-Unis] ; Chris A. Myers [États-Unis] ; Hetunandan Kamisetty [États-Unis] ; Patrick Blair [États-Unis] ; Ian A. Wilson [États-Unis] ; David Baker [États-Unis]Source :
- Nature biotechnology [ 1087-0156 ] ; 2012.
Abstract
We show that comprehensive sequence-function maps obtained by deep sequencing can be used to reprogram interaction specificity and to leapfrog over bottlenecks in affinity maturation by combining many individually small contributions not detectable in conventional approaches. We use this approach to optimize two computationally designed inhibitors against H1N1 influenza hemagglutinin and, in both cases, obtain variants with subnanomolar binding affinity. The most potent of these, a 51-residue protein, is broadly cross-reactive against all influenza group 1 hemagglutinins, including human H2, and neutralizes H1N1 viruses with a potency that rivals that of several human monoclonal antibodies, demonstrating that computational design followed by comprehensive energy landscape mapping can generate proteins with potential therapeutic utility.
Url:
DOI: 10.1038/nbt.2214
PubMed: 22634563
PubMed Central: 3638900
Affiliations:
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Whitehead</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Chevalier, Aaron" sort="Chevalier, Aaron" uniqKey="Chevalier A" first="Aaron" last="Chevalier">Aaron Chevalier</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Song, Yifan" sort="Song, Yifan" uniqKey="Song Y" first="Yifan" last="Song">Yifan Song</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Dreyfus, Cyrille" sort="Dreyfus, Cyrille" uniqKey="Dreyfus C" first="Cyrille" last="Dreyfus">Cyrille Dreyfus</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Fleishman, Sarel J" sort="Fleishman, Sarel J" uniqKey="Fleishman S" first="Sarel J" last="Fleishman">Sarel J. 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Whitehead</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Chevalier, Aaron" sort="Chevalier, Aaron" uniqKey="Chevalier A" first="Aaron" last="Chevalier">Aaron Chevalier</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Song, Yifan" sort="Song, Yifan" uniqKey="Song Y" first="Yifan" last="Song">Yifan Song</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Dreyfus, Cyrille" sort="Dreyfus, Cyrille" uniqKey="Dreyfus C" first="Cyrille" last="Dreyfus">Cyrille Dreyfus</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Fleishman, Sarel J" sort="Fleishman, Sarel J" uniqKey="Fleishman S" first="Sarel J" last="Fleishman">Sarel J. Fleishman</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="De Mattos, Cecilia" sort="De Mattos, Cecilia" uniqKey="De Mattos C" first="Cecilia" last="De Mattos">Cecilia De Mattos</name><affiliation wicri:level="2"><nlm:aff id="A3">Naval Health Research Center, San Diego, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Naval Health Research Center, San Diego, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Myers, Chris A" sort="Myers, Chris A" uniqKey="Myers C" first="Chris A" last="Myers">Chris A. Myers</name><affiliation wicri:level="2"><nlm:aff id="A3">Naval Health Research Center, San Diego, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Naval Health Research Center, San Diego, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Kamisetty, Hetunandan" sort="Kamisetty, Hetunandan" uniqKey="Kamisetty H" first="Hetunandan" last="Kamisetty">Hetunandan Kamisetty</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author><author><name sortKey="Blair, Patrick" sort="Blair, Patrick" uniqKey="Blair P" first="Patrick" last="Blair">Patrick Blair</name><affiliation wicri:level="2"><nlm:aff id="A3">Naval Health Research Center, San Diego, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Naval Health Research Center, San Diego, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A" last="Wilson">Ian A. Wilson</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Baker, David" sort="Baker, David" uniqKey="Baker D" first="David" last="Baker">David Baker</name><affiliation wicri:level="4"><nlm:aff id="A1">Department of Biochemistry, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="A4">Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Howard Hughes Medical Institute, University of Washington, Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region><settlement type="city">Seattle</settlement></placeName><orgName type="university">Université de Washington</orgName></affiliation></author></analytic><series><title level="j">Nature biotechnology</title><idno type="ISSN">1087-0156</idno><idno type="eISSN">1546-1696</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">We show that comprehensive sequence-function maps obtained by deep sequencing can be used to reprogram interaction specificity and to leapfrog over bottlenecks in affinity maturation by combining many individually small contributions not detectable in conventional approaches. We use this approach to optimize two computationally designed inhibitors against H1N1 influenza hemagglutinin and, in both cases, obtain variants with subnanomolar binding affinity. The most potent of these, a 51-residue protein, is broadly cross-reactive against all influenza group 1 hemagglutinins, including human H2, and neutralizes H1N1 viruses with a potency that rivals that of several human monoclonal antibodies, demonstrating that computational design followed by comprehensive energy landscape mapping can generate proteins with potential therapeutic utility.</p></div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Washington (État)</li></region><settlement><li>Seattle</li></settlement><orgName><li>Université de Washington</li></orgName></list><tree><country name="États-Unis"><region name="Washington (État)"><name sortKey="Whitehead, Timothy A" sort="Whitehead, Timothy A" uniqKey="Whitehead T" first="Timothy A" last="Whitehead">Timothy A. Whitehead</name></region><name sortKey="Baker, David" sort="Baker, David" uniqKey="Baker D" first="David" last="Baker">David Baker</name><name sortKey="Baker, David" sort="Baker, David" uniqKey="Baker D" first="David" last="Baker">David Baker</name><name sortKey="Blair, Patrick" sort="Blair, Patrick" uniqKey="Blair P" first="Patrick" last="Blair">Patrick Blair</name><name sortKey="Chevalier, Aaron" sort="Chevalier, Aaron" uniqKey="Chevalier A" first="Aaron" last="Chevalier">Aaron Chevalier</name><name sortKey="De Mattos, Cecilia" sort="De Mattos, Cecilia" uniqKey="De Mattos C" first="Cecilia" last="De Mattos">Cecilia De Mattos</name><name sortKey="Dreyfus, Cyrille" sort="Dreyfus, Cyrille" uniqKey="Dreyfus C" first="Cyrille" last="Dreyfus">Cyrille Dreyfus</name><name sortKey="Fleishman, Sarel J" sort="Fleishman, Sarel J" uniqKey="Fleishman S" first="Sarel J" last="Fleishman">Sarel J. Fleishman</name><name sortKey="Kamisetty, Hetunandan" sort="Kamisetty, Hetunandan" uniqKey="Kamisetty H" first="Hetunandan" last="Kamisetty">Hetunandan Kamisetty</name><name sortKey="Myers, Chris A" sort="Myers, Chris A" uniqKey="Myers C" first="Chris A" last="Myers">Chris A. Myers</name><name sortKey="Song, Yifan" sort="Song, Yifan" uniqKey="Song Y" first="Yifan" last="Song">Yifan Song</name><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A" last="Wilson">Ian A. Wilson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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