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: Contribution to journalArticle

  • 170 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
Monoclonal antibodies
Hemagglutinins
Viruses
Monoclonal Antibodies
Therapeutics
hemagglutinin I

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: Contribution to journalArticle

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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