Massively parallel de novo protein design for targeted therapeutics

Aaron Chevalier, Daniel-Adriano Silva, Gabriel J. Rocklin, Derrick R. Hicks, Renan Vergara, Patience Murapa, Steffen M. Bernard, Lu Zhang, Kwok-Ho Lam, Guorui Yao, Christopher D. Bahl, Shin-Ichiro Miyashita, Inna Goreshnik, James T. Fuller, Merika T. Koday, Cody M. Jenkins, Tom Colvin, Lauren Carter, Alan Bohn, Cassie M. Bryan, D. Alejandro Fernández-Velasco, Lance Stewart, Min Dong, Xuhui Huang, Rongsheng Jin, Ian A. Wilson, Deborah H. Fuller and David Baker ()
Additional contact information
Aaron Chevalier: University of Washington
Daniel-Adriano Silva: University of Washington
Gabriel J. Rocklin: University of Washington
Derrick R. Hicks: University of Washington
Renan Vergara: University of Washington
Patience Murapa: University of Washington
Steffen M. Bernard: The Scripps Research Institute
Lu Zhang: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences
Kwok-Ho Lam: University of California
Guorui Yao: University of California
Christopher D. Bahl: University of Washington
Shin-Ichiro Miyashita: Boston Children’s Hospital
Inna Goreshnik: University of Washington
James T. Fuller: University of Washington
Merika T. Koday: University of Washington
Cody M. Jenkins: University of Washington
Tom Colvin: University of Washington
Lauren Carter: University of Washington
Alan Bohn: University of Washington
Cassie M. Bryan: University of Washington
D. Alejandro Fernández-Velasco: Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria
Lance Stewart: Institute for Protein Design, University of Washington
Min Dong: Boston Children’s Hospital
Xuhui Huang: The Hong Kong University of Science and Technology
Rongsheng Jin: University of California
Ian A. Wilson: The Scripps Research Institute
Deborah H. Fuller: University of Washington
David Baker: University of Washington

Nature, 2017, vol. 550, issue 7674, 74-79

Abstract: Abstract De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

Date: 2017
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DOI: 10.1038/nature23912

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