Application of the Inverse-Electron-Demand Diels-Alder Reaction for Metabolic Glycoengineering

Abstract

The inverse electron-demand Diels-Alder (IEDDA or DAinv) reaction is an emerging bioorthogonal ligation reaction that finds application in all areas of chemistry and chemical biology. In this review we highlight its application in metabolic glycoengineering (MGE). MGE is a versatile tool to introduce unnatural sugar derivatives that are modified with a chemical reporter group into cellular glycans. The IEDDA reaction can then be used to modify the chemical reporter group allowing, for instance, the visualization or isolation of glycoconjugates. During the last years, many different sugar derivatives as well as reporter groups have been published. These probes are summarized, and their chemical and biological properties are discussed. Furthermore, we discuss examples of MGE and subsequent IEDDA reaction that highlight its suitability for application within living systems.

An Advanced ‘clickECM’ That Can be Modified by the Inverse‐Electron‐Demand Diels‐Alder Reaction

“…The labeling efficiency in MGE experiments depends on both the amount of reporter group incorporated and the chemical reactivity in the bioorthogonal ligation reaction. [ 16 , 17c ] In case of the terminal alkenes, an increasing length of the side chain leads to higher reactivity in the IEDDA reaction. At the same time, it can be expected that the metabolic acceptance of the GalNAc derivative is lower with increasing length of the side chain.…”

“…[15] The latter has found widespread application as a bioorthogonal ligation reaction in various applications including MGE. [16] Dienophiles that undergo an IEDDA reaction with tetrazines and that have been used for MGE include terminal alkenes [17] and strained cyclic alkenes, such as cyclopropenes, [18] bicyclononynes, [19] and norbornenes. [20] These dienophiles can have markedly different reaction kinetics enabling various applications including sequential modifications with different tetrazines.…”

Metabolic glycoengineering – exploring glycosylation with bioorthogonal chemistry

“…For a more complete treatment of this topic, the reader is referred to recent reviews on bioorthogonal chemistry. [28][29][30][31][32][33][34]…”

Click Chemistry Hydrogels for Extrusion Bioprinting: Progress, Challenges, and Opportunities

“…While the electron-poor dieneophile is combined with an electron-rich diene in a conventional DA reaction, the inverse of this reaction (commonly termed inverse electron-demand Diels–Alder (IEDDA) chemistry) represents an attractive strategy for hydrogel synthesis due to its faster reaction rate under physiological pH and temperature. ,, IEDDA cross-linking most commonly typically involves reactions between phenyltetrazine derivatives and strained cycloalkenes (i.e., norbornene , ). While IEDDA-cross-linked hydrogels have been shown to be cytocompatible and useful for peptide immobilization, the hydrogels formulated using the phenyltetrazine functionality and the dienophile are considerably more thermodynamically stable due to the irreversibility of the IEDDA cross-link resulting from the generation of nitrogen during the synthesis. − The degradability can be specifically engineered into the backbone polymers (i.e., via the inclusion of disulfide bonds).…”