Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing

Timothy A. Whitehead, Aaron Chevalier, Yifan Song, Cyrille Dreyfus, Sarel J. Fleishman, Cecilia De Mattos, Chris A. Myers, Hetunandan Kamisetty, Patrick Blair, Ian A. Wilson, David Baker

    Research output: Research - peer-reviewArticle

    • 142 Citations

    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.

    LanguageEnglish (US)
    Pages543-548
    Number of pages6
    JournalNature Biotechnology
    Volume30
    Issue number6
    DOIs
    StatePublished - Jun 2012

    Profile

    High-Throughput Nucleotide Sequencing
    Human Influenza
    Proteins
    H1N1 Subtype Influenza A Virus
    Hemagglutinins
    Monoclonal Antibodies
    Therapeutics
    hemagglutinin I
    Viruses
    Monoclonal antibodies

    ASJC Scopus subject areas

    • Applied Microbiology and Biotechnology
    • Biotechnology
    • Molecular Medicine
    • Bioengineering
    • Biomedical Engineering

    Cite this

    Whitehead, T. A., Chevalier, A., Song, Y., Dreyfus, C., Fleishman, S. J., De Mattos, C., ... Baker, D. (2012). Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nature Biotechnology, 30(6), 543-548. DOI: 10.1038/nbt.2214

    Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. / Whitehead, Timothy A.; Chevalier, Aaron; Song, Yifan; Dreyfus, Cyrille; Fleishman, Sarel J.; De Mattos, Cecilia; Myers, Chris A.; Kamisetty, Hetunandan; Blair, Patrick; Wilson, Ian A.; Baker, David.

    In: Nature Biotechnology, Vol. 30, No. 6, 06.2012, p. 543-548.

    Research output: Research - peer-reviewArticle

    Whitehead, TA, Chevalier, A, Song, Y, Dreyfus, C, Fleishman, SJ, De Mattos, C, Myers, CA, Kamisetty, H, Blair, P, Wilson, IA & Baker, D 2012, 'Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing' Nature Biotechnology, vol 30, no. 6, pp. 543-548. DOI: 10.1038/nbt.2214
    Whitehead TA, Chevalier A, Song Y, Dreyfus C, Fleishman SJ, De Mattos C et al. Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nature Biotechnology. 2012 Jun;30(6):543-548. Available from, DOI: 10.1038/nbt.2214
    Whitehead, Timothy A. ; Chevalier, Aaron ; Song, Yifan ; Dreyfus, Cyrille ; Fleishman, Sarel J. ; De Mattos, Cecilia ; Myers, Chris A. ; Kamisetty, Hetunandan ; Blair, Patrick ; Wilson, Ian A. ; Baker, David. / Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. In: Nature Biotechnology. 2012 ; Vol. 30, No. 6. pp. 543-548
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