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.

Functionalized 2-Hydroxybenzaldehyde-PEG Modules as Portable Tags for the Engagement of Protein Lysine ϵ-Amino Groups / G. Sacco, S. Stammwitz, L. Belvisi, L. Pignataro, A. Dal Corso, C. Gennari. - In: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY. - ISSN 1434-193X. - 2021:11(2021), pp. 1763-1767. [10.1002/ejoc.202100160]

Functionalized 2-Hydroxybenzaldehyde-PEG Modules as Portable Tags for the Engagement of Protein Lysine ϵ-Amino Groups

G. Sacco
Primo
;
L. Belvisi;L. Pignataro;A. Dal Corso
Penultimo
;
C. Gennari
Ultimo
2021

Abstract

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.
Aldehydes; Conjugation; Regioselectivity; Schiff bases; Skattebø l formylation
Settore CHIM/06 - Chimica Organica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/834572
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