Single‐Step N‐Terminal Modification of Proteins via a Bio‐Inspired Copper(II)‐Mediated Aldol Reaction

• Published in: Chemistry : a European journal Vol. 28; no. 47; pp. e202201677 - n/a
• Main Authors: Hanaya, Kengo, Yamoto, Kaho, Taguchi, Kazuaki, Matsumoto, Kazuaki, Higashibayashi, Shuhei, Sugai, Takeshi
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 22.08.2022
• Subjects: Activity recognition; Aldehydes; aldol reaction; Amino acids; Biopharmaceuticals; Carbon; Chemical modification; Copper; Epidermal growth factor; Growth factors; Peptides; protein modifications; Proteins; Room temperature; Trastuzumab
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202201677

The chemical modification of proteins is an effective technique for manipulating the properties and functions of proteins, and for creating protein‐based materials. The N‐terminus is a promising target for single‐site modification that provides modified proteins with uniform structures and properties. In this paper, a copper(II)‐mediated aldol reaction with 2‐pyridinecarboxaldehyde (2‐PC) derivatives is proposed as an operationally simple method to selectively modify the N‐terminus of peptides and proteins at room temperature and physiological pH. The copper(II) ion activates the N‐terminal amino acids by complexation with an imine of the N‐terminal amino acid and 2‐PCs, realizing the selective formation of the nucleophilic intermediate at the N‐terminus. This results in a stable carbon‐carbon bond between the 2‐PCs and the α‐carbon of various N‐terminal amino acids. The reaction is applied to four different proteins, including biopharmaceuticals such as filgrastim and trastuzumab. The modified trastuzumab retains the human epidermal growth factor receptor 2 recognition activity. 2‐Pydinecarboxaldehyde derivatives undergoes unique aldol reaction at the N‐terminus of peptides and proteins in the presence of a copper(II) salt under mild conditions. Peptides and proteins are readily modified with useful functional groups or reactive handles in a single step.