Accurate de novo design of hyperstable constrained peptides

Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes 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 molecu...

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Main Authors:	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, 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
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161715/

id	pubmed-5161715
recordtype	oai_dc
spelling	pubmed-51617152017-03-14 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 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 Article Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes 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 de novo design of conformationally-restricted peptides, and the use of these methods to design 15–50 residue disulfide-crosslinked and heterochiral N-C backbone-cyclized peptides. These peptides are exceptionally stable to thermal and chemical denaturation, and twelve experimentally-determined X-ray and NMR structures are nearly identical to the computational models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs. 2016-09-14 2016-10-20 /pmc/articles/PMC5161715/ /pubmed/27626386 http://dx.doi.org/10.1038/nature19791 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Reprints and permissions information is available at www.nature.com/reprints.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
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 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
spellingShingle	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 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
author_facet	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 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
author_sort	Bhardwaj, Gaurav
title	Accurate de novo design of hyperstable constrained peptides
title_short	Accurate de novo design of hyperstable constrained peptides
title_full	Accurate de novo design of hyperstable constrained peptides
title_fullStr	Accurate de novo design of hyperstable constrained peptides
title_full_unstemmed	Accurate de novo design of hyperstable constrained peptides
title_sort	accurate de novo design of hyperstable constrained peptides
description	Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes 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 de novo design of conformationally-restricted peptides, and the use of these methods to design 15–50 residue disulfide-crosslinked and heterochiral N-C backbone-cyclized peptides. These peptides are exceptionally stable to thermal and chemical denaturation, and twelve experimentally-determined X-ray and NMR structures are nearly identical to the computational models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161715/
_version_	1613787230234476544

Accurate de novo design of hyperstable constrained peptides

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