Elsevier

Current Opinion in Biotechnology

Volume 53, October 2018, Pages 106-114
Current Opinion in Biotechnology

In vivo catalyzed new-to-nature reactions

https://doi.org/10.1016/j.copbio.2017.12.008Get rights and content

Bioorthogonal chemistry largely relies on the use of abiotic metals to catalyze new-to-nature reactions in living systems. Over the past decade, metal complexes and metal-encapsulated systems such as nanoparticles have been developed to unravel the reactivity of transition metals, including ruthenium, palladium, iridium, copper, iron, and gold in biological systems. Thanks to these remarkable achievements, abiotic catalysts are able to fluorescently label cells, uncage or form cytotoxic drugs and activate enzymes in cellulo/vivo. Recently, strategies for the delivery of such catalysts to specific cell types, cell compartments or proteins were established. These studies reveal the enormous potential of this emerging field and its application in both medicinal chemistry and in synthetic biology.

Introduction

Over the past decade, abiotic transition metal-catalyzed reactions have successfully been introduced into living cells and organisms. With in vivo applications in mind, several challenges were identified and addressed: (i) overcome the inherent cytotoxicity of the abiotic catalyst, (ii) ensure the efficient metal uptake by the cell and (iii) circumvent the deactivation of the catalyst by thiols, proteins and other cell components [1]. To address these issues, several strategies were developed: (i) metals were incorporated into nanoparticles or embedded in microspheres and resins (see sections: ‘Palladium nanoparticles’ and ‘Copper and gold nanoparticles’; the catalyzed reactions are summarized in Table 1) or (ii) used as homogeneous metal complexes (see sections: ‘Homogenous ruthenium catalysts’, ‘Homogenous palladium catalysts’ and ‘Homogenous iron, iridium and gold catalysts’; the catalyzed reactions and complexes are collected in Table 2). Most reactions developed to date are based on either a cleavage, or a cross-coupling reaction. As a result, a variety of in vivo functions were established that are schematically presented in Figure 1 including: (i) fluorescent labeling of cells, cell compartments and proteins, (ii) synthesis of cytotoxic agents and (iii) enzyme rescue. Several excellent reviews cover bioorthogonal reactions [2, 3, 4, 5, 6, 7] or bioorthogonal protein labeling and protein chemistry [8, 9, 10, 11, 12•]. This review focuses on bioorthogonal transition metal-catalyzed reactions in cellulo (inside single cells in a cell culture) and in vivo (inside living organisms), highlighting recent developments towards therapeutic applications.

Section snippets

Palladium nanoparticles

The use of metal nanoparticles (NPs) for in cellulo catalysis was first demonstrated by the Bradley group [13]. They exploited the biocompatibility of polystyrene microspheres [14] by entrapping Pd-NPs, creating fluorescently-labeled Pd0-microspheres [13, 15]. These Pd0-catalysts cleave allyloxycarbonyl (alloc)-groups, leading to the uncaging of fluorescent rhodamine 110 (R110) within the cytoplasm of HeLa cells (Table 1, entry 1) [13]. Moreover, these Pd0-loaded microspheres also catalyze the

Copper and gold nanoparticles

The range of metal-NPs was recently broadened to include Cu [20, 21] and Au [22•, 23••], thus expanding the in vivo catalytic repertoire. Although CuI-catalyzed azide–alkyne cycloaddition (CuAAC) has been known since 2002 [24, 25], it was hardly used in vivo due to its marked cytotoxicity [26]. The incorporation of Cu into aspartate-containing polyolefins [20] or entrapping Cu in TentaGel resin [21], contributed to overcoming these biocompatibility issues. On the one hand, Cu-based NPs convert

Homogenous ruthenium catalysts

Streu's and Meggers’ seminal work on in cellulo catalyzed Ru-reactions laid the foundation of bioorthogonal organometallic chemistry [27]. In 2006, they suggested that the complex [Cp*Ru(cod)Cl] Ru1 (Cp*=pentamethylcyclopentadienyl, cod = 1,5-cyclooctadiene, Table 2, entry 1) catalyzes the uncaging of alloc-protected R110 inside HeLa cells, while not affecting the cell viability [27]. In 2014 and 2017, they reported on significantly more active Ru-pianostool complexes Ru2–Ru6 (Table 2, entries 1

Homogeneous palladium catalysts

To the best of our knowledge, the first homogeneous Pd-catalyzed reaction in cellulo was reported by Lin et al. [41]. A copper-free Sonogashira cross-coupling reaction was used to selectively label homopropargylglycine inside E. coli cells. Fluorescein iodide was coupled to the metabolically incorporated homopropargyglycine, by a newly discovered Pd-complex Pd1 (Table 2, entry 9) [41].

Subsequently, unnatural amino acids (UAAs) were genetically encoded by amber stop codon suppression [42, 43]

Homogenous iron, iridium and gold catalysts

Besides Ru-complexes and Pd-complexes, other metals have been employed for intracellular labeling: an iron(III) meso-tetraarylporphin Fe1 (Table 2, entry 16) was shown to catalyze azide reduction leading to the release of R110 in HeLa cells [52]. The Ir-complex Ir1 (Table 2, entry 17) reduces an aldehyde leading to the release of a fluorescent Bodipy-OH inside NIH-3T3 cells [53]. A more sophisticated Au-catalyzed approach was developed by Tanaka et al. [54••]. They relied on an Au-complex

Conclusions

Since 2014, the field of metal-catalyzed bioorthogonal reactions has made significant progress. Initially, it was demonstrated that metal-NPs and metal complexes can uncage or synthesize drugs in cellulo/vivo. Subsequently, the specificity of these metal-based platforms was considerably improved. Now, it is possible to target specific organs, cells, cell compartments and certain proteins. Thanks to these efforts, one can envision the possibility of targeting and killing cells as well as gaining

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

TRW thanks the ERC (The DrEAM) and the NCCR Molecular Systems engineering for generous support of his work in this field. JGR thanks EMBO for a Long-Term fellowship (EMBO ALTF 194-2017).

References (54)

  • P.K. Sasmal et al.

    Metal complex catalysis in living biological systems

    Chem Commun (Camb)

    (2013)
  • D.M. Patterson et al.

    Finding the right (bioorthogonal) chemistry

    ACS Chem Biol

    (2014)
  • J. Li et al.

    Development and application of bond cleavage reactions in bioorthogonal chemistry

    Nat Chem Biol

    (2016)
  • C.D. Spicer et al.

    Selective chemical protein modification

    Nat Commun

    (2014)
  • M. Yang et al.

    Transition metal-mediated bioorthogonal protein chemistry in living cells

    Chem Soc Rev

    (2014)
  • F. Schwizer et al.

    Artificial metalloenzymes: reaction scope and optimization strategies

    Chem Rev

    (2017)
  • R.M. Yusop et al.

    Palladium-mediated intracellular chemistry

    Nat Chem

    (2011)
  • L.M. Alexander et al.

    Investigation of microsphere-mediated cellular delivery by chemical, microscopic and gene expression analysis

    Mol Biosyst

    (2010)
  • A. Unciti-Broceta et al.

    Synthesis of polystyrene microspheres and functionalization with Pd(0) nanoparticles to perform bioorthogonal organometallic chemistry in living cells

    Nat Protoc

    (2012)
  • J.T. Weiss et al.

    Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach

    Nat Commun

    (2014)
  • J. Clavadetscher et al.

    In-cell dual drug synthesis by cancer-targeting palladium catalysts

    Angew Chem Int Ed Engl

    (2017)
  • M.A. Miller et al.

    Nano-palladium is a cellular catalyst for in vivo chemistry

    Nat Commun

    (2017)
  • J. Hrkach et al.

    Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile

    Sci Transl Med

    (2012)
  • Y. Bai et al.

    A Highly efficient single-chain metal–organic nanoparticle catalyst for alkyne–azide “click” reactions in water and in cells

    J Am Chem Soc

    (2016)
  • J. Clavadetscher et al.

    Copper catalysis in living systems and in situ drug synthesis

    Angew Chem Int Ed Engl

    (2016)
  • A.M. Perez-Lopez et al.

    Gold-triggered uncaging chemistry in living systems

    Angew Chem Int Ed Engl

    (2017)
  • G.Y. Tonga et al.

    Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts

    Nat Chem

    (2015)

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