A biocompatible stapling reaction for in situ generation of constrained peptides

Date

2020-11-04

Authors

Morewood, Richard
Nitsche, Christoph

Journal Title

Journal ISSN

Volume Title

Publisher

Royal Society of Chemistry

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.

Description

Keywords

Citation

Source

Chemical science

Type

Journal article

Book Title

Entity type

Access Statement

Open Access

License Rights

Creative Commons Attribution 3.0

Restricted until

Downloads