Computation-Guided Rational Design of a Peptide Motif That Reacts with Cyanobenzothiazoles Via Internal Cysteine-Lysine Relay

Overview

Journal J Org Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2018 May 18

PMID 29771122

Citations 6

Authors

Samantha G L Keyser

Ashley Utz

Carolyn R Bertozzi

Affiliations

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Abstract

Site-selective protein modification based on covalent reactions of peptide tags and small molecules is a key capability for basic research as well as for the development of new therapeutic bioconjugates. Here, we describe the computation-guided rational design of a cysteine- and lysine-containing 11-residue peptide sequence that reacts with 2-cyanobenzothiazole (CBT) derivatives. Our data show that the cysteine residue reversibly reacts with the nitrile group on the CBT moiety to form an intermediate thioimidate, which undergoes irreversible SN transfer to the lysine residue, yielding an amidine-linked product. The concepts outlined herein lay a foundation for future development of peptide tags in the context of site-selective modification of lysine residues within engineered microenvironments.

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