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Bioorthogonal chemistry

Linghui Qian, Chong-Jing Zhang, Ji'en Wu, Shao Q Yao
Challenges exist in the development of potent and selective small-molecule inhibitors against caspase-1. Herein, by making use of the copper-free strain-promoted alkyne-azide cycloaddition (SPAAC) reaction between difluorinated cyclooctynes (DIFOs) and various azide-containing compounds, we showed for the first time that potential caspase-1 inhibitors could be rapidly synthesized. The resulting fused bicyclic compounds structurally resembled the central portion (P2 -P3 ) of Pralnacasan (a well-known small molecule caspase-1 inhibitor), with diversity at the P4 -position of the parental inhibitor conveniently installed from the azide component...
November 24, 2016: Chemistry: a European Journal
Kévin Renault, Laurie-Anne Jouanno, Antoine Lizzul-Jurse, Pierre-Yves Renard, Cyrille Sabot
Fluorogenic reactions are largely underrepresented in the toolbox of chemoselective ligations despite their tremendous potential, particularly in chemical biology and biochemistry. In this respect, we have investigated in full detail the fluorescence behaviour of the azaphthalamide, a scaffold which is generated through a hetero-Diels-Alder reaction of 5-alkoxyoxazole and maleimide derivatives under mild conditions that are compatible with, among others, peptide chemistry. The scope and limitations of such a fluorogenic labelling strategy were examined through four distinct applications, which target enzymatic activities or bioorthogonal reactions...
November 9, 2016: Chemistry: a European Journal
Dilini N Kekulandara, Kusal T G Samarasinghe, Dhanushka N P Munkanatta Godage, Young-Hoon Ahn
Protein glutathionylation is one of the major cysteine oxidative modifications in response to reactive oxygen species (ROS). We recently developed a clickable glutathione approach for detecting glutathionylation by using a glutathione synthetase mutant (GS M4) that synthesizes azido-glutathione (γGlu-Cys-azido-Ala) in situ in cells. In order to demonstrate the versatility of clickable glutathione and to increase the chemical tools for detecting glutathionylation, we sought to develop clickable glutathione that uses tetrazine-alkene bioorthogonal chemistry...
November 4, 2016: Organic & Biomolecular Chemistry
Belén Rubio-Ruiz, Jason T Weiss, Asier Unciti-Broceta
Bioorthogonal uncaging strategies have recently emerged as an experimental therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chemistry using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer...
October 27, 2016: Journal of Medicinal Chemistry
Heebeom Koo, Sei Kwang Hahn, Seok Hyun Yun
We demonstrate a chemically detachable cell-glue system based on linkers containing disulfide bonds as well as functional groups for metabolic glycoengineering and bioorthogonal click chemistry. Azide groups are generated on the cell surface by metabolic glycoengineering, and they are further modified into tetrazine (Tz) or trans-cyclooctene (TCO) using rationally designed cross-linkers. When the Tz-modified and TCO-modified cells are mixed together, cell gluing between these two cell groups is established by Tz-TCO click chemistry...
October 27, 2016: Bioconjugate Chemistry
Tao Peng, Howard C Hang
Over the past years, fluorescent proteins (e.g., green fluorescent proteins) have been widely utilized to visualize recombinant protein expression and localization in live cells. Although powerful, fluorescent protein tags are limited by their relatively large sizes and potential perturbation to protein function. Alternatively, site-specific labeling of proteins with small-molecule organic fluorophores using bioorthogonal chemistry may provide a more precise and less perturbing method. This approach involves site-specific incorporation of unnatural amino acids (UAAs) into proteins via genetic code expansion, followed by bioorthogonal chemical labeling with small organic fluorophores in living cells...
November 2, 2016: Journal of the American Chemical Society
Jorin Hoogenboom, Nathalja Berghuis, Dario Cramer, Rene Geurts, Han Zuilhof, Tom Wennekes
BACKGROUND: Carbohydrates, also called glycans, play a crucial but not fully understood role in plant health and development. The non-template driven formation of glycans makes it impossible to image them in vivo with genetically encoded fluorescent tags and related molecular biology approaches. A solution to this problem is the use of tailor-made glycan analogs that are metabolically incorporated by the plant into its glycans. These metabolically incorporated probes can be visualized, but techniques documented so far use toxic copper-catalyzed labeling...
October 10, 2016: BMC Plant Biology
Catherine Su Hui Teo, Remigiusz A Serwa, Peter O'Hare
We used pulse-labeling with the methionine analogue homopropargylglycine (HPG) to investigate spatiotemporal aspects of protein synthesis during herpes simplex virus (HSV) infection. In vivo incorporation of HPG enables subsequent selective coupling of fluorochrome-capture reagents to newly synthesised proteins. We demonstrate that HPG labeling had no effect on cell viability, on accumulation of test early or late viral proteins, or on overall virus yields. HPG pulse-labeling followed by SDS-PAGE analysis confirmed incorporation into newly synthesised proteins, while parallel processing by in situ cycloaddition revealed new insight into spatiotemporal aspects of protein localisation during infection...
October 2016: PLoS Pathogens
Joanna B Pawlak, Brett J Hos, Michel J van de Graaff, Otty A Megantari, Nico Meeuwenoord, Herman S Overkleeft, Dmitri V Filippov, Ferry Ossendorp, Sander I van Kasteren
Antigen recognition followed by the activation of cytotoxic T-cells (CTLs) is a key step in adaptive immunity, resulting in clearance of viruses and cancers. The repertoire of peptides that have the ability to bind to the major histocompatibility type-I (MHC-I) is enormous, but the available approaches to study the diversity of the peptide repertoire on a cell are limited. Here we explore the use of bioorthogonal chemistry to quantify specific peptide-MHC-I complexes (pMHC-I) on cells. We show that modifying epitope peptides with bioorthogonal groups in surface accessible positions allows wild-type-like MHC-I binding and bioorthogonal ligation using fluorogenic chromophores in combination with a Cu(I)-catalyzed Huisgen cycloaddition reaction...
October 5, 2016: ACS Chemical Biology
Kathrin Elisabeth Witzke, Kristin Rosowski, Christian Müller, Maike Ahrens, Martin Eisenacher, Dominik A Megger, Jürgen Knobloch, Andrea R Koch, Thilo Bracht, Barbara Sitek
Quantitative secretome analyses are a high-performance tool for the discovery of physiological and pathophysiological changes in cellular processes. However, serum supplements in cell culture media limit secretome analyses, but serum depletion often leads to cell starvation and consequently biased results. To overcome these limiting factors, we investigated a model of T cell activation (Jurkat cells) and performed an approach for the selective enrichment of secreted proteins from conditioned medium utilizing metabolic marking of newly synthesized glycoproteins...
October 3, 2016: Journal of Proteome Research
Abdolreza Yazdani, Holly Bilton, Alyssa Vito, Afaf R Genady, Stephanie M Rathmann, Zainab Ahmad, Nancy Janzen, Shannon Czorny, Brian M Zeglis, Lynn C Francesconi, John F Valliant
A high yield synthesis of a novel, small molecule, bisphosphonate-modified trans-cyclooctene (TCO-BP, 2) that binds to regions of active bone metabolism and captures functionalized tetrazines in vivo, via the bioorthogonal inverse electron demand Diels-Alder (IEDDA) cycloaddition, was developed. A (99m)Tc-labeled derivative of 2 demonstrated selective localization to shoulder and knee joints in a biodistribution study in normal mice. Compound 2 reacted rapidly with a (177)Lu-labeled tetrazine in vitro, and pretargeting experiments in mice, using 2 and the (177)Lu-labeled tetrazine, yielded high activity concentrations in shoulder and knee joints, with minimal uptake in other tissues...
October 5, 2016: Journal of Medicinal Chemistry
Donghyun Lim, Wan Gi Byun, Ja Young Koo, Hankum Park, Seung Bum Park
MicroRNAs (miRNAs) regulate gene expression by targeting protein-coding transcripts that are involved in various cellular processes. Thus, miRNA biogenesis has been recognized as a novel therapeutic target. Especially, the let-7 miRNA family is well-known for its tumor suppressor functions and is downregulated in many cancer cells. Lin28 protein binds to let-7 miRNA precursors to inhibit their maturation. Herein, we developed a FRET-based, high-throughput screening system to identify small-molecule inhibitors of the Lin28-let-7 interaction...
October 7, 2016: Journal of the American Chemical Society
Pablo Mateos-Gil, Sebastian Letschert, Sören Doose, Markus Sauer
Besides its function as a passive cell wall, the plasma membrane (PM) serves as a platform for different physiological processes such as signal transduction and cell adhesion, determining the ability of cells to communicate with the exterior, and form tissues. Therefore, the spatial distribution of PM components, and the molecular mechanisms underlying it, have important implications in various biological fields including cell development, neurobiology, and immunology. The existence of confined compartments in the plasma membrane that vary on many length scales from protein multimers to micrometer-size domains with different protein and lipid composition is today beyond all questions...
2016: Frontiers in Cell and Developmental Biology
Arne H Smits, Annika Borrmann, Mark Roosjen, Jan C M van Hest, Michiel Vermeulen
Epitope-tagging is an effective tool to facilitate protein enrichment from crude cell extracts. Traditionally, N- or C-terminal fused tags are employed, which, however, can perturb protein function. Unnatural amino acids (UAAs) harboring small reactive handles can be site-specifically incorporated into proteins, thus serving as a potential alternative for conventional protein tags. Here, we introduce Click-MS, which combines the power of site-specific UAA incorporation, bioorthogonal chemistry, and quantitative mass spectrometry-based proteomics to specifically enrich a single protein of interest from crude mammalian cell extracts...
October 17, 2016: ACS Chemical Biology
Borja Belda-Palazón, Alejandro Ferrando, Rosa Farràs
The development of novel bioorthogonal reactives that can be used to tag biomolecules in vivo has revolutionized the studies of cellular and molecular biology. Among those novel reactive substances, amino acid analogs can be used to label nascent proteins, thus opening new avenues for measuring protein translation rates in vivo with a limited manipulation of the sample. Here, we describe the use of Click-chemistry to tag and separate newly synthesized proteins in mammalian cells that can be used, coupled with western analysis, to estimate the translation rate of any protein of interest...
2016: Methods in Molecular Biology
María Tomás-Gamasa, Miguel Martínez-Calvo, José R Couceiro, José L Mascareñas
The development of transition metal catalysts capable of promoting non-natural transformations within living cells can open significant new avenues in chemical and cell biology. Unfortunately, the complexity of the cell makes it extremely difficult to translate standard organometallic chemistry to living environments. Therefore, progress in this field has been very slow, and many challenges, including the possibility of localizing active metal catalysts into specific subcellular sites or organelles, remain to be addressed...
September 7, 2016: Nature Communications
R Serfling, I Coin
The site-specific incorporation of unnatural amino acids (Uaas) via genetic code expansion provides a powerful method to introduce synthetic moieties into specific positions of a protein directly in the live cell. The technique, first developed in bacteria, is nowadays widely applicable in mammalian cells. In general, different Uaas are incorporated with different efficiency. By comparing the incorporation efficiency of several Uaas recently designed for bioorthogonal chemistry, we present here a facile dual-fluorescence assay to evaluate relative yields of Uaa incorporation...
2016: Methods in Enzymology
Aleksandra Pałasz
This review is an endeavor to highlight the progress in the inverse-electron-demand hetero-Diels-Alder reactions of 1-oxa-1,3-butadienes in recent years. The huge number of examples of 1-oxadienes cycloadditions found in the literature clearly demonstrates the incessant importance of this transformation in pyran ring synthesis. This type of reaction is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in structuring of carbohydrate and other natural products...
June 2016: Topics in Current Chemistry (Journal)
T Carell, M Vrabel, M Yang, Y Yang, P R Chen, J Dommerholt, F P J T Rutjes, F L van Delft, A Herner, Q Lin, H Wu, N K Devaraj, S Kath-Schorr
No abstract text is available yet for this article.
June 2016: Topics in Current Chemistry (Journal)
T Carell, M Vrabel, M Yang, Y Yang, P R Chen, J Dommerholt, F P J T Rutjes, F L van Delft, A Herner, Q Lin, H Wu, N K Devaraj, S Kath-Schorr
No abstract text is available yet for this article.
April 2016: Topics in Current Chemistry (Journal)
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