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A biocompatible stapling reaction for in situ generation of constrained peptides

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Abstract

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 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.

Graphical abstract: A biocompatible stapling reaction for in situ generation of constrained peptides

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Article information


Submitted
16 Sep 2020
Accepted
03 Nov 2020
First published
04 Nov 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

A biocompatible stapling reaction for in situ generation of constrained peptides

R. Morewood and C. Nitsche, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC05125J

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