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Nature. 2016 Oct 20;538(7625):329-335. doi: 10.1038/nature19791. Epub 2016 Sep 14.

Accurate de novo design of hyperstable constrained peptides.

Author information

1
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
2
Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA.
3
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
4
Seattle Structural Genomics Center for Infectious Diseases, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
5
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, USA.
6
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
7
Global Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark.
8
Cyrus Biotechnology, Seattle, Washington 98109, USA.
9
Department of Chemistry, New York University, New York, New York 10003, USA.
10
Department of Biology, New York University, New York, New York 10003, USA.
11
Center for Computational Biology, Simons Foundation, New York, New York 10010, USA.
12
Applied Mathematics and Statistics and Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, USA.
13
Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.

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.

PMID:
27626386
PMCID:
PMC5161715
DOI:
10.1038/nature19791
[Indexed for MEDLINE]
Free PMC Article

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