A Naturally Encoded Dipeptide Handle for Bioorthogonal Chan–Lam Coupling

1. INTRODUCTION 1.1 Generalities and Context 1.2 C-N Bond Formation via Cross-Coupling Reactions 1.3 C-N Bond Formation via Nucleophile-Electrophile Cross-Coupling 1.4 C-N Bond Formation via Nucleophile-Nucleophile Cross-Coupling 2. DISCUSSION 2.1 Discovery 2.2 Development of Reaction Conditions 2.3 A General Mechanistic Description of the Chan-Lam Reaction 2.4 Reactions Variables and Selection of Reaction Conditions 3. SCOPE OF THE CHAN-LAM AMINATION 3.1 Organoboron Variation 3.2 Aryl Amines (Anilines) 3.3 Heteroaryl Amines (Heterocyclic Anilines) 3.4 Alkyl Amines 3.5 Amides 3.6 NH-Heterocycles 3.7 C-N Bond Formation to non-NH-Nucleophiles 3.8 Sulfonamides and Sulfoximes 3.9 Sequential Processes 3.10 C-N Bond Formation on Nucleobases and Peptides 4. MECHANISM 4.1 Historical Context 4.2 Mechanistic Investigations in the Etherification Reaction 4.3 Mechanistic Investigations in the Amination Reaction 4.4 Mechanistic Investigations in the Amination Reaction: Ligand-based Systems 4.5 Mechanism Summary

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“…The selective aryl/alkenylation was also replicated in more challenging systems using cell lysates. 203…”

Section: C−n Bond Formation On Nucleobases and Peptidesmentioning

confidence: 99%

Mechanistic Development and Recent Applications of the Chan–Lam Amination

et al. 2019

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“…Using this method, despite the low yield (∼25%), the authors demonstrated a single modification of a backbone N−H bond in lysozyme. This approach has also been used for selective modification of N-terminal pyroglutamate (a naturally occurring PTM)-His tagged proteins in E. coli cell lysates 55 and photocaging protein backbones. 56 Recognition-driven chemical reactions also provide a powerful way to site-specifically modify proteins (discussed in more detail in the following section).…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Chemistry for Covalent Modification of Endogenous/Native Proteins: From Test Tubes to Complex Biological Systems

2018

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Chemical modification of proteins provides powerful tools to realize a broad range of exciting biological applications, including the development of new classes of biopharmaceuticals and functional studies of individual proteins in complex biological systems. Numerous strategies for linking desired chemical probes with target proteins have been developed in the last two decades, with most exploiting genetic protein engineering and/or bio-orthogonal chemistry that utilizes unnatural amino acids incorporated into proteins. Modification of native proteins in test tubes and biological contexts by site-specific and target-selective approaches remains challenging because appropriate organic chemistry to carry out such modifications is currently limited. Nonetheless, a variety of promising strategies have appeared recently that address this grand challenge in chemical biology. These new chemistries yield native protein-based well-defined bioconjugations, specific labeling of endogenous proteins in various biological crude milieus, and the establishment of chemical proteomics as a new research area in protein science. In this Perspective, we focus on recent remarkable progress in chemistry for native protein modification. We survey chemical characteristics of the methods and describe briefly these advanced applications to address unsolved biological issues. Current limitations and future directions of this research field are also discussed.

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“…2,23 In contrast, selective modification of histidine, which is commonly found in enzyme active sites and metal-binding sites, 24,25 remains underexplored. Because the imidazole side chain of histidine is a good metal ligand, metal coordination can enable protein modification through metal-directed covalent labeling proximal to the histidine group 26,27 or direct noncovalent metal-histidine complexation, [28][29][30][31][32] the latter of which can be labile under biological contexts or mass spectrometry conditions. However, histidine is a useful catalytic component owing to its ability to serve as both a good nucleophile and leaving group, but this character also makes it difficult to form stable bonds with the imidazole side chain through electrophilic functionalization.…”

Section: Introductionmentioning

confidence: 99%

Bioinspired Thiophosphorodichloridate Reagents for Chemoselective Histidine Bioconjugation

2019

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Site-selective bioconjugation to native protein residues is a powerful tool for protein functionalization, with cysteine and lysine side chains being the most common points for attachment owing to their high nucleophilicity. We now report a strategy for histidine modification using thiophosphorodichloridate reagents that mimic post-translational histidine phosphorylation, enabling fast and selective labeling of protein histidines under mild conditions where various payloads can be introduced via copper-assisted alkyne-azide cycloaddition (CuAAC) chemistry. We establish that these reagents are particularly effective at covalent modification of His-tags, which are common motifs to facilitate protein purification, as illustrated by selective attachment of polyarginine cargoes to enhance the uptake of proteins into living cells. This work provides a starting point for probing and enhancing protein function using histidine-directed chemistry.

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A Naturally Encoded Dipeptide Handle for Bioorthogonal Chan–Lam Coupling

Abstract: Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Cited by 14 publications

References 29 publications

Mechanistic Development and Recent Applications of the Chan–Lam Amination

Mechanistic Development and Recent Applications of the Chan–Lam Amination

Chemistry for Covalent Modification of Endogenous/Native Proteins: From Test Tubes to Complex Biological Systems

Bioinspired Thiophosphorodichloridate Reagents for Chemoselective Histidine Bioconjugation

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