Design strategies for bioorthogonal smart probes

Shieh, Peyton; Bertozzi, Carolyn R.

doi:10.1039/c4ob01632g

Cited by 201 publications

(164 citation statements)

References 128 publications

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“…1–4 Fluorogenicity, which leads to good signal-to-noise ratio, is highly desirable for protein labeling in a complex biological environment. Fluorogenic bioorthogonal reactions, where the removal of unreacted reagents is not necessary, could simplify and, in some situations, enable real-time imaging experiments in live cells.…”

Section: Introductionmentioning

confidence: 99%

Fluorogenic protein labeling using a genetically encoded unstrained alkene

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Fluorogenic protein labeling using a genetically encoded unstrained alkene

et al. 2017

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“…flavopeptin, Figure 2). 24 Due to their reactivity towards nucleophiles and biological rarity, aldehydes have been exploited for bioconjugation 25,26 with numerous examples with oligonucleotides 27,28 and glycoproteins. 29,30 These bioconjugations are typically carried out with aminooxy or hydrazide groups to afford oxime or hydrazone linkages, respectively.…”

Section: Introductionmentioning

confidence: 99%

Targeting Reactive Carbonyls for Identifying Natural Products and Their Biosynthetic Origins

et al. 2016

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Natural products serve important roles as drug candidates and as tools for chemical biology. However, traditional natural product discovery, largely based on bioassay-guided approaches, is biased towards abundant compounds and rediscovery rates are high. Orthogonal methods to facilitate discovery of new natural products are thus needed, and herein we describe an isotope tag-based expansion of reactivity-based natural product screening to address these shortcomings. Reactivity-based screening is a directed discovery approach in which a specific reactive handle on the natural product is targeted by a chemoselective probe to enable its detection by mass spectrometry. In this study, we have developed an aminooxy-containing probe to guide the discovery of aldehyde- and ketone-containing natural products. To facilitate the detection of labeling events, the probe was dibrominated, imparting a unique isotopic signature to distinguish labeled metabolites from spectral noise. As a proof of concept, the probe was then utilized to screen a collection of bacterial extracts, leading to the identification of a new analog of antipain, deimino-antipain. The bacterial producer of deimino-antipain was sequenced and the responsible biosynthetic gene cluster was identified by bioinformatic analysis and heterologous expression. These data reveal the previously undetermined genetic basis for a well-known family of aldehyde-containing, peptidic protease inhibitors, including antipain, chymostatin, leupeptin, elastatinal, and microbial alkaline protease inhibitor (MAPI), which have been widely used for over 40 years.

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“…However, a limitation of this approach lies in the need of excess labelling reagents, which often give rise to high background fluorescence. Bioorthogonal conjugations that are fluorogenic 12 would overcome this limitation and greatly expand the scope of applications in biology.…”

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confidence: 99%

Fluorogenic diazaborine formation of semicarbazide with designed coumarin derivatives

2017

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Bioorthogonal fluorogenic reactions serve as enabling tools in research and biotechnology. Herein we describe fluorogenic conjugations of semicarbazide with courmarin derivatives that incorporate a 2-acetylphenylboronic acid motif. These designed courmarins rapidly conjugate with semicarbazide to give diazaborine products with significantly enhanced fluorescence. To demonstrate potential applications of this fluorogenic reaction, we synthesized a semicarbazide-presenting amino acid D-Dap-Scz, which readily incorporates into the cell wall of Staphalococcus aureus and serves as a handle for conjugation with the coumarins. The fluorogenic conjugation of the coumarins to cell surface semicarbazide enables facile visualization of D-Dap-Scz treated bacteria.

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Design strategies for bioorthogonal smart probes

Cited by 201 publications

References 128 publications

Fluorogenic protein labeling using a genetically encoded unstrained alkene

Fluorogenic protein labeling using a genetically encoded unstrained alkene

Targeting Reactive Carbonyls for Identifying Natural Products and Their Biosynthetic Origins

Fluorogenic diazaborine formation of semicarbazide with designed coumarin derivatives

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