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Functionalized 2‐Hydroxybenzaldehyde‐PEG Modules as Portable Tags for the Engagement of Protein Lysine ϵ‐Amino Groups
Author(s) -
Sacco Giovanni,
Stammwitz Simon,
Belvisi Laura,
Pignataro Luca,
Dal Corso Alberto,
Gennari Cesare
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202100160
Subject(s) - chemistry , lysine , ligand (biochemistry) , polyethylene glycol , electrophile , covalent bond , combinatorial chemistry , amine gas treating , peg ratio , context (archaeology) , small molecule , amino acid , azide , molecule , stereochemistry , organic chemistry , biochemistry , receptor , economics , catalysis , paleontology , finance , biology
The formation of reversible‐covalent interactions between a small‐molecule ligand and its protein target is emerging as a general strategy to design binders with increased affinity. In this context, 2‐hydroxybenzaldehyde (2HB) has been recently proposed as suitable electrophilic tag to engage primary amines, such as the ϵ‐amino group of lysine residues, in remarkably stable imines. Lys residues are often expressed in high amounts on protein surfaces and in the proximity of ligand binding sites, and a fine‐tuning of the chemical connection between the ligand and 2HB is fundamental for the affinity gain. Herein we report the synthesis of four 2HB tags functionalized with a short polyethylene glycol (PEG) spacer and a suitable reactive ‘handle’ (alkyne, azide, carboxylic acid and amine, respectively) for their conjugation to virtually any type of small molecule ligand.