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A biocompatible stapling reaction for in situ generation of constrained peptides

Morewood, Richard; Nitsche, Christoph

Description

Constrained peptides are promising next-generation therapeutics. Peptide stapling is a particularly attractive technique to generate constrained macrocycles with improved biological activity and metabolic stability. We introduce a biocompatible two-component stapling approach based on the reagent 2,6-dicyanopyridine and a pseudo-cysteine amino acid. Stapling can proceed either directly on-resin during solid-phase synthesis or following isolation of the linear peptide. The stapling reaction is...[Show more]

dc.contributor.authorMorewood, Richard
dc.contributor.authorNitsche, Christoph
dc.date.accessioned2022-06-27T03:14:12Z
dc.date.available2022-06-27T03:14:12Z
dc.identifier.issn2041-6520
dc.identifier.urihttp://hdl.handle.net/1885/268511
dc.description.abstractConstrained peptides are promising next-generation therapeutics. Peptide stapling is a particularly attractive technique to generate constrained macrocycles with improved biological activity and metabolic stability. We introduce a biocompatible two-component stapling approach based on the reagent 2,6-dicyanopyridine and a pseudo-cysteine amino acid. Stapling can proceed either directly on-resin during solid-phase synthesis or following isolation of the linear peptide. The stapling reaction is orthogonal to natural amino acid side chains and completes in aqueous solution at physiological pH, enabling its direct use in biochemical assays. We performed a small screening campaign of short peptides targeting the Zika virus protease NS2B-NS3, allowing the direct comparison of linear with in situ stapled peptides. A stapled screening hit showed over 28-fold stronger inhibition than its linear analogue, demonstrating the successful identification of constrained peptide inhibitors.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherRoyal Society of Chemistry
dc.rights© 2021 The Author(s). Published by the Royal Society of Chemistry
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.sourceChemical science
dc.titleA biocompatible stapling reaction for in situ generation of constrained peptides
dc.typeJournal article
local.identifier.citationvolume12
dc.date.issued2020-11-04
local.identifier.ariespublicationa383154xPUB19041
local.publisher.urlhttps://pubs.rsc.org/en/content/articlelanding/2021/sc/d0sc05125j
local.type.statusPublished Version
local.contributor.affiliationNitsche, Christoph, Research School of Chemistry, The Australian National University
dc.relationhttp://purl.org/au-research/grants/arc/DE190100015
local.bibliographicCitation.issue2
local.bibliographicCitation.startpage669
local.bibliographicCitation.lastpage674
local.identifier.doi10.1039/d0sc05125j
dcterms.accessRightsOpen Access
dc.provenanceThis article is licensed under a Creative Commons Attribution 3.0 Unported Licence 2021 The Author(s). Published by the Royal Society of Chemistry
dc.rights.licenseCreative Commons Attribution 3.0
CollectionsANU Research Publications

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