Click Chemistry and Bioorthogonal Reactions: Unprecedented Selectivity in the Labeling of Biological Molecules

Abstract

In recent years, a number of bioorthogonal reactions have been developed, exemplified by click chemistry, that enable the efficient formation of a specific product, even within a highly complex chemical environment. While the exquisite selectivity and reliability of these transformations have led to their broad application in diverse research areas, they have proven to be particularly beneficial to biological studies. In this regard, the ability to rationally incorporate reactive tags onto a biomolecular target and subsequently achieve high selectivity in tag derivatization within a complex biological sample has revolutionized the toolbox that is available for addressing fundamental issues. Herein, an introduction to the impact of click chemistry and other bioorthogonal reactions on the study of biological systems is presented. This includes discussion of the philosophy behind click chemistry, the details and benefits of bioorthogonal reactions that have been developed, and examples of recent innovative approaches that have effectively exploited these transformations to study cellular processes. For the latter, the impacts of bioorthogonal reactions on drug design (i.e., in situ combinatorial drug design), biomolecule labeling and detection (site-specific derivatization of proteins, viruses, sugars, DNA, RNA, and lipids), and the recent strategy of activity-based protein profiling are highlighted.

γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin

“…We substituted the phenyl group on the right-hand side of E2012 with a benzophenone photoreactive group to affect covalent capture of the binding partner(s) upon UV irradiation. In addition, we replaced the methyl group of the methoxyphenyl moiety with a propargyl group to enable click chemistry-mediated conjugation with reporter groups (39,40). The resulting clickable photoprobe E2012-BPyne lowered A␤42 and A␤40 and increased A␤38 with efficacy similar to the parent GSM E2012 in a cell-free HeLa membrane assay using C100-FLAG as a recombinant APP substrate ( Fig.…”

Covalent Cell Surface Functionalization of Human Fetal Osteoblasts for Tissue Engineering

“…[1][2][3][4][5] The chemical motifs involved in these reactions include peptide sequence with specific side chain combinations, carbonyl moieties for condensation with aminooxy or hydrazides probes, and azides for Staudinger ligation with triarylphosphines and cycloadditions to alkynes. 6,7 The biocompatibility of these reactions provides efficient tools for the modification of proteins, the labeling of enzymes, the metabolic labeling of cell-surface glycans and lipids within their native cellular environment and thus allows to study the biological processes in which these biomolecules are involved.…”

La chimie-click débusque les substrats d’ADAM10

“…Ces réactions sont d'une grande sélectivité, permettant de coupler divers types de molécules fonctionnalisées sans interférer avec l'environnement biologique, et ont donc trouvé de nombreuses applications en biologie. Elles ont par exemple été utilisées pour le développement de nouvelles drogues, le marquage de biomolécules, ou différents types de marquages métaboliques (protéines, ADN, lipides) [6].…”

“…Il est donc important d'étudier les médiateurs libérés par les cellules de l'immunité innée ainsi que les conditions environnementales qui déter-minent leur production. L'IL-22 est sécrétée par les cellules de l'immunité et exerce des propriétés hépatoprotectrices [6]. Kudira et al [2] se sont intéressés dans ce travail à identifier les cellules productrices de cette cytokine et les mécanismes de régulation de sa production au cours de la régéné-ration après hépatectomie partielle.…”