New Phenol Esters for Efficient pH-Controlled Amine Acylation of Peptides, Proteins, and Sepharose Beads in Aqueous Media

Kim B. Jensen*, Jesper Hyldal Mikkelsen, Simon P. Jensen, Steffen Kidal, Gitte Friberg, Troels Skrydstrup, Magnus B.F. Gustafsson*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

This paper describes the discovery, synthesis, and use of novel water-soluble acylation reagents for efficient and selective modification, cross-linking, and labeling of proteins and peptides, as well as for their use in the effective modification of sepharose beads under pH control in aqueous media. The reagents are based on a 2,4-dichloro-6-sulfonic acid phenol ester core combined with a variety of linker structures. The combination of these motifs leads to an ideal balance between hydrolytic stability and reactivity. At high pH, good to excellent conversions (up to 95%) and regioselectivity (up to 99:1 Nϵ/Nα amine ratio) in the acylation were realized, exemplified by the chemical modification of incretin peptides and insulin. At neutral pH, an unusually high preference toward the N-terminal phenylalanine in an insulin derivative was observed (>99:1 Nα/Nϵ), which is up until now unprecedented in the literature for more elaborate reagents. In addition, the unusually high hydrolytic stability of these reagents and their ability to efficiently react at low concentrations (28 μM or 0.1 mg/mL) are exemplified with a hydroxy linker-based reagent and are a unique feature of this work.

Original languageEnglish
JournalBioconjugate Chemistry
Volume33
Issue1
Pages (from-to)172-179
Number of pages8
ISSN1043-1802
DOIs
Publication statusPublished - Jan 2022

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