Accurate de novo design of hyperstable constrained peptides

Gaurav Bhardwaj, Vikram Khipple Mulligan, Christopher D. Bahl, Jason M. Gilmore, Peta J. Harvey, Olivier Cheneval, Garry W. Buchko, Surya V. S. R. K. Pulavarti, Quentin Kaas, Alexander Eletsky, Po-Ssu Huang, William A. Johnsen, Per Jr Greisen, Gabriel J. Rocklin, Yifan Song, Thomas W. Linsky, Andrew Watkins, Stephen A. Rettie, Xianzhong Xu, Lauren P. Carter, Richard Bonneau, James M. Olson, Evangelos Coutsias, Colin E. Correnti, Thomas Szyperski, David J. Craik and David Baker ()
Additional contact information
Gaurav Bhardwaj: University of Washington
Vikram Khipple Mulligan: University of Washington
Christopher D. Bahl: University of Washington
Jason M. Gilmore: University of Washington
Peta J. Harvey: Institute for Molecular Bioscience, The University of Queensland
Olivier Cheneval: Institute for Molecular Bioscience, The University of Queensland
Garry W. Buchko: Seattle Structural Genomics Center for Infectious Diseases, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory
Surya V. S. R. K. Pulavarti: State University of New York at Buffalo
Quentin Kaas: Institute for Molecular Bioscience, The University of Queensland
Alexander Eletsky: State University of New York at Buffalo
Po-Ssu Huang: University of Washington
William A. Johnsen: Fred Hutchinson Cancer Research Center
Per Jr Greisen: University of Washington
Gabriel J. Rocklin: University of Washington
Yifan Song: University of Washington
Thomas W. Linsky: University of Washington
Andrew Watkins: New York University
Stephen A. Rettie: Institute for Protein Design, University of Washington
Xianzhong Xu: State University of New York at Buffalo
Lauren P. Carter: Institute for Protein Design, University of Washington
Richard Bonneau: New York University
James M. Olson: Fred Hutchinson Cancer Research Center
Evangelos Coutsias: Applied Mathematics and Statistics and Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook
Colin E. Correnti: Fred Hutchinson Cancer Research Center
Thomas Szyperski: State University of New York at Buffalo
David J. Craik: Institute for Molecular Bioscience, The University of Queensland
David Baker: University of Washington

Nature, 2016, vol. 538, issue 7625, 329-335

Abstract: Abstract Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for accurate de novo design of conformationally restricted peptides, and the use of these methods to design 18–47 residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N–C backbone-cyclized. Both genetically encodable and non-canonical peptides are exceptionally stable to thermal and chemical denaturation, and 12 experimentally determined X-ray and NMR structures are nearly identical to the computational design models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.

Date: 2016
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DOI: 10.1038/nature19791

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