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Title: Accurate de novo design of hyperstable constrained peptides

Abstract

Covalently-crosslinked peptides present attractive opportunities for developing new therapeutics. Lying between small molecule and protein therapeutics in size, natural crosslinked peptides play critical roles in signaling, virulence and immunity. Engineering novel peptides with precise control over their three-dimensional structures is a significant challenge. Here we describe the development of computational methods for de novo design of conformationally-restricted peptides, and the use of these methods to design hyperstable disulfide-stabilized miniproteins, heterochiral peptides, and N-C cyclic peptides. Experimentally-determined X-ray and NMR structures for 12 of the designs are nearly identical to the computational models. The computational design methods and stable scaffolds provide the basis for a new generation of peptide-based drugs.

Authors:
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Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1340751
Report Number(s):
PNNL-SA-117706
Journal ID: ISSN 0028-0836; 49153; 48683; 453040220
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature (London); Journal Volume: 538; Journal Issue: 7625
Country of Publication:
United States
Language:
English
Subject:
protein-based therapeutics; structural biology; NMR spectroscopy; drug-design; Rosetta calculations; Environmental Molecular Sciences Laboratory

Citation Formats

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. Accurate de novo design of hyperstable constrained peptides. United States: N. p., 2016. Web. doi:10.1038/nature19791.
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. Accurate de novo design of hyperstable constrained peptides. United States. doi:10.1038/nature19791.
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". United States. doi:10.1038/nature19791.
@article{osti_1340751,
title = {Accurate de novo design of hyperstable constrained peptides},
author = {Bhardwaj, Gaurav and Mulligan, Vikram Khipple and Bahl, Christopher D. and Gilmore, Jason M. and Harvey, Peta J. and Cheneval, Olivier and Buchko, Garry W. and Pulavarti, Surya V. S. R. K. and Kaas, Quentin and Eletsky, Alexander and Huang, Po-Ssu and Johnsen, William A. and Greisen, Per Jr and Rocklin, Gabriel J. and Song, Yifan and Linsky, Thomas W. and Watkins, Andrew and Rettie, Stephen A. and Xu, Xianzhong and Carter, Lauren P. and Bonneau, Richard and Olson, James M. and Coutsias, Evangelos and Correnti, Colin E. and Szyperski, Thomas and Craik, David J. and Baker, David},
abstractNote = {Covalently-crosslinked peptides present attractive opportunities for developing new therapeutics. Lying between small molecule and protein therapeutics in size, natural crosslinked peptides play critical roles in signaling, virulence and immunity. Engineering novel peptides with precise control over their three-dimensional structures is a significant challenge. Here we describe the development of computational methods for de novo design of conformationally-restricted peptides, and the use of these methods to design hyperstable disulfide-stabilized miniproteins, heterochiral peptides, and N-C cyclic peptides. Experimentally-determined X-ray and NMR structures for 12 of the designs are nearly identical to the computational models. The computational design methods and stable scaffolds provide the basis for a new generation of peptide-based drugs.},
doi = {10.1038/nature19791},
journal = {Nature (London)},
number = 7625,
volume = 538,
place = {United States},
year = 2016,
month = 9
}