Site-selective tyrosine bioconjugation via photoredox catalysis for native-to-bioorthogonal protein transformation

Li, Beryl X.; Kim, Daniel K.; Bloom, Steven; Huang, Richard Y.‐C.; Qiao, Jennifer X.; Ewing, William R.; Oblinsky, Daniel G.; Scholes, Gregory D.; MacMillan, David W. C.

doi:10.1038/s41557-021-00733-y

Cited by 91 publications

(75 citation statements)

References 42 publications

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“…When exposed to blue light (34 W, 440 nm) in the presence of lumiflavin as the photocatalyst, the phenoxazine ring was converted to the electrophilic N -centred radical 228 that coupled selectively with the electron-rich phenol groups of tyrosines. In addition, the presence of two formyl groups on the phenoxazine ring allowed for further functionalization of the conjugates by classical hydrazine ligation [ 257 ]. Most notably, this strategy led to exquisite site-selectivity on nine different native proteins with molecular weights ranging from 5.8 to 77.0 kDa.…”

Section: Site-selective Strategiesmentioning

confidence: 99%

An overview of chemo- and site-selectivity aspects in the chemical conjugation of proteins

et al. 2022

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The bioconjugation of proteins—that is, the creation of a covalent link between a protein and any other molecule—has been studied for decades, partly because of the numerous applications of protein conjugates, but also due to the technical challenge it represents. Indeed, proteins possess inner physico-chemical properties—they are sensitive and polynucleophilic macromolecules—that make them complex substrates in conjugation reactions. This complexity arises from the mild conditions imposed by their sensitivity but also from selectivity issues, viz the precise control of the conjugation site on the protein. After decades of research, strategies and reagents have been developed to address two aspects of this selectivity: chemoselectivity—harnessing the reacting chemical functionality—and site-selectivity—controlling the reacting amino acid residue—most notably thanks to the participation of synthetic chemistry in this effort. This review offers an overview of these chemical bioconjugation strategies, insisting on those employing native proteins as substrates, and shows that the field is active and exciting, especially for synthetic chemists seeking new challenges.

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Section: Site-selective Strategiesmentioning

confidence: 99%

An overview of chemo- and site-selectivity aspects in the chemical conjugation of proteins

et al. 2022

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“…Yet another example of proximity labeling was used to label lectins by employing beads bearing lactose functionalized with a Ru‐catalyst ( Figure 2 ,C ) [21] . Most recently, lumiflavin ( Figure 1, LF ) was shown to undergo selective SET with phenoxazine dialdehyde to produce a radical which in turn reacts with tyrosine in a protein to install a bioorthogonal formyl group for further functionalization ( Figure 2 ,D ) [22] . A salient feature of this chemistry is its sensitivity to the microenvironment of the tyrosine, enabling the selective labeling of a single tyrosine from among 26 tyrosine residue on a complex protein framework.…”

Section: Click and Clip The Backbone Of Chemical Biologymentioning

confidence: 99%

“…[21] Most recently, lumiflavin (Figure 1, LF) was shown to undergo selective SET with phenoxazine dialdehyde to produce a radical which in turn reacts with tyrosine in a protein to install a bioorthogonal formyl group for further functionalization (Figure 2,D). [22] A salient feature of this chemistry is its sensitivity to the microenvironment of the tyrosine, enabling the selective labeling of a single tyrosine from among 26 tyrosine residue on a complex protein framework. This example clearly illustrates the opportunity of chemistry that can discriminate between unreactive tyrosine deactivated by π-cation interaction and more reaction tyrosine activated by hydrogenbond-donation (SOMOphilic).…”

Section: Photooxidative Clicks and Clipsmentioning

confidence: 99%

Photocatalysis in Chemical Biology: Extending the Scope of Optochemical Control and Towards New Frontiers in Semisynthetic Bioconjugates and Biocatalysis

Liu

Watson

Winssinger

2021

Helvetica Chimica Acta

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“…There are several examples for Tyr-selective SPMs complementary to enzymatic methodologies: − for example, Barbas , reported ortho - C -functionalization of the Tyr phenol with triazolinediones, which was later advanced further to enzymatic and electrochemical Tyr SPMs by Nakamura − and Gouin, respectively. Lei and MacMillan also developed electrochemical and photochemical ortho - C -functionalization for Tyr SPMs, respectively, using phenothiazine derivatives. For O-functionalization, Francis and Lee and Kim reported a palladium-complex-mediated allylic substitution and sulfur fluoride exchange chemistry (SuFEx), respectively.…”

Section: Introductionmentioning

confidence: 99%

Protein Modification at Tyrosine with Iminoxyl Radicals

et al. 2021

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Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologicallyrelevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins, whereas the reversible modification of Tyr with 1o switched protein function on and off in an enzyme and in a monoclonal antibody by modification and deconjugation processes. ASSOCIATED CONTENTSupporting Information. Experimental procedures, characterization data, computational procedure, and data. The Supporting Information is available free of charge at https://pubs.acs.org.

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Site-selective tyrosine bioconjugation via photoredox catalysis for native-to-bioorthogonal protein transformation

Cited by 91 publications

References 42 publications

An overview of chemo- and site-selectivity aspects in the chemical conjugation of proteins

An overview of chemo- and site-selectivity aspects in the chemical conjugation of proteins

Photocatalysis in Chemical Biology: Extending the Scope of Optochemical Control and Towards New Frontiers in Semisynthetic Bioconjugates and Biocatalysis

Protein Modification at Tyrosine with Iminoxyl Radicals

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