Cargando…

Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides

Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report...

Descripción completa

Detalles Bibliográficos
Autores principales: Cromm, Philipp M., Schaubach, Sebastian, Spiegel, Jochen, Fürstner, Alois, Grossmann, Tom N., Waldmann, Herbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834642/
https://www.ncbi.nlm.nih.gov/pubmed/27075966
http://dx.doi.org/10.1038/ncomms11300
_version_ 1782427521764032512
author Cromm, Philipp M.
Schaubach, Sebastian
Spiegel, Jochen
Fürstner, Alois
Grossmann, Tom N.
Waldmann, Herbert
author_facet Cromm, Philipp M.
Schaubach, Sebastian
Spiegel, Jochen
Fürstner, Alois
Grossmann, Tom N.
Waldmann, Herbert
author_sort Cromm, Philipp M.
collection PubMed
description Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets.
format Online
Article
Text
id pubmed-4834642
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-48346422016-05-02 Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides Cromm, Philipp M. Schaubach, Sebastian Spiegel, Jochen Fürstner, Alois Grossmann, Tom N. Waldmann, Herbert Nat Commun Article Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets. Nature Publishing Group 2016-04-14 /pmc/articles/PMC4834642/ /pubmed/27075966 http://dx.doi.org/10.1038/ncomms11300 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Cromm, Philipp M.
Schaubach, Sebastian
Spiegel, Jochen
Fürstner, Alois
Grossmann, Tom N.
Waldmann, Herbert
Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
title Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
title_full Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
title_fullStr Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
title_full_unstemmed Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
title_short Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
title_sort orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small gtpase-targeting bicyclic peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834642/
https://www.ncbi.nlm.nih.gov/pubmed/27075966
http://dx.doi.org/10.1038/ncomms11300
work_keys_str_mv AT crommphilippm orthogonalringclosingalkyneandolefinmetathesisforthesynthesisofsmallgtpasetargetingbicyclicpeptides
AT schaubachsebastian orthogonalringclosingalkyneandolefinmetathesisforthesynthesisofsmallgtpasetargetingbicyclicpeptides
AT spiegeljochen orthogonalringclosingalkyneandolefinmetathesisforthesynthesisofsmallgtpasetargetingbicyclicpeptides
AT furstneralois orthogonalringclosingalkyneandolefinmetathesisforthesynthesisofsmallgtpasetargetingbicyclicpeptides
AT grossmanntomn orthogonalringclosingalkyneandolefinmetathesisforthesynthesisofsmallgtpasetargetingbicyclicpeptides
AT waldmannherbert orthogonalringclosingalkyneandolefinmetathesisforthesynthesisofsmallgtpasetargetingbicyclicpeptides