Accurate de novo design of hyperstable constrained peptides

Bhardwaj, Gaurav, Mulligan, Vikram Khipple, Bahl, Christopher D., Gilmore, Jason M., Harvey, Peta J., Cheneval, Olivier, Buchko, Garry W., Pulavarti, Surya V. S. R. K., Kaas, Quentin, Eletsky, Alexander, Huang, Po-Ssu, Johnsen, William A., Greisen, Per Jr, Rocklin, Gabriel J., Song, Yifan, Linsky, Thomas W., Watkins, Andrew, Rettie, Stephen A., Xu, Xianzhong, Carter, Lauren P., Bonneau, Richard, Olson, James M., Coutsias, Evangelos, Correnti, Colin E., Szyperski, Thomas, Craik, David J. and Baker, David (2016) Accurate de novo design of hyperstable constrained peptides. Nature, 538 7625: 329-335. doi:10.1038/nature19791


Author Bhardwaj, Gaurav
Mulligan, Vikram Khipple
Bahl, Christopher D.
Gilmore, Jason M.
Harvey, Peta J.
Cheneval, Olivier
Buchko, Garry W.
Pulavarti, Surya V. S. R. K.
Kaas, Quentin
Eletsky, Alexander
Huang, Po-Ssu
Johnsen, William A.
Greisen, Per Jr
Rocklin, Gabriel J.
Song, Yifan
Linsky, Thomas W.
Watkins, Andrew
Rettie, Stephen A.
Xu, Xianzhong
Carter, Lauren P.
Bonneau, Richard
Olson, James M.
Coutsias, Evangelos
Correnti, Colin E.
Szyperski, Thomas
Craik, David J.
Baker, David
Title Accurate de novo design of hyperstable constrained peptides
Formatted title
Accurate de novo design of hyperstable constrained peptides
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
1476-4687
Publication date 2016-09-14
Year available 2016
Sub-type Article (original research)
DOI 10.1038/nature19791
Open Access Status Not yet assessed
Volume 538
Issue 7625
Start page 329
End page 335
Total pages 21
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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