Les Publications

Les publications de l’UMR

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Egloff, C., Weltin, D., Calligaro, C., Mosser, M., Nothisen, M., Rémy, JS., and Wagner, A.

Bio-specific and bio-orthogonal chemistries to switch-off the quencher of a FRET-based fluorescent probe: application to living-cell biothiol imaging, Chem. Commun., 2014, 50, 10049-10051.

We report the first molecular system that is responsive to both a bio-specific and a bio-orthogonal stimulus. This dual activation process was applied to the design of a biothiol-specific FRET-based fluorescent probe that could be turned-on via an original concept of quencher bleaching.

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Plougastel, L., Koniev, O., Specklin, S., Decuypere, E., Créminon, C., Buisson, D., Wagner, A., Kolodych, S., and Taran, F.

4-Halogeno-sydnones for fast strain promoted cycloaddition with cyclooctynes, Chem. Commun., 2014, 50, 9376-9378.

New sydnone derivatives have been synthesized and screened for their capacity to undergo fast copper-free cycloaddition reaction with bicyclo-[6.1.0]-nonyne. The influences of substitution in positions N-3 and C-4 of sydnones have been particularly studied leading to the identification of highly reactive partners for bio-orthogonal ligation reactions.

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Martinčič; R., Kuzmanovski, I., Wagner, A., and Novic, M.

Development of models for prediction of the antioxidant activity of derivatives of natural compounds, Anal. Chim. Acta, 2015, 868, 23–35.

Antioxidants are important for maintaining the appropriate balance between oxidizing and reducing species in the body and thus preventing oxidative stress. Many natural compounds are being screened for their possible antioxidant activity. It was found that a mushroom pigment Norbadione A, which is a pulvinic acid derivative, shows an antioxidant activity; the same was found for other pulvinic acid derivatives and structurally related coumarines. Based on the results of in vitro studies performed on these compounds as a part of this study quantitative structure–activity relationship (QSAR) predictive models were constructed using multiple linear regression, counter-propagation artificial neural networks and support vector regression (SVR). The models have been developed in accordance with current QSAR guidelines, including the assessment of the models applicability domains. A new approach for the graphical evaluation of the applicability domain for SVR models is suggested. The developed models show sufficient predictive abilities for the screening of virtual libraries for new potential antioxidants.

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Kolodych, S., Koniev, O., Baatarkhuu, Z., Bonnefoy, JY., Debaene, F., Cianférani, S., Van Dorsselaer, A., and Wagner, A.

CBTF: new amine-to-thiol coupling reagent for preparation of antibody conjugates with increased plasma stability, Bioconjugate Chem., 2015, 26, 197–200.

Amine-to-thiol coupling is the most common route for the preparation of antibody–drug conjugates (ADC). It is usually achieved by using heterobifunctional reagents possessing an activated ester at one end and a maleimide group at the other. However, maleimide-based conjugates were recently revealed to have limited stability in blood circulation, which can compromise therapeutic efficacy of the conjugate. To address this issue, we have developed a heterobifunctional reagent, sodium 4-((4-(cyanoethynyl)benzoyl)oxy)-2,3,5,6-tetrafluorobenzenesulfonate (CBTF), for amine-to-thiol coupling. It comprises a recently described 3-arylpropionitrile (APN) function in replacement of maleimide and allows for the preparation of remarkably stable conjugates. A series of antibody–dye conjugates have been prepared using this reagent and shown superior stability in human blood plasma compared to maleimide-derived conjugates.

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Jacques, S. A., Kuhn, I., Koniev, O., Schuber, F., Lund, F. E., Wagner, A., Muller-Steffner, H., and Kellenberger, E.

Discovery of potent inhibitors of Schistosoma mansoni NAD+ catabolizing enzyme, J. Med. Chem., 2015, 58, 3582–3592.

The blood fluke Schistosoma mansoni is the causative agent of the intestinal form of schistosomiasis (or bilharzia). Emergence of Schistosoma mansoni with reduced sensitivity to praziquantel, the drug currently used to treat this neglected disease, has underlined the need for development of new strategies to control schistosomiasis. Our ability to screen drug libraries for antischistosomal compounds has been hampered by the lack of validated S. mansoni targets. In the present work, we describe a virtual screening approach to identify inhibitors of S. mansoni NAD+ catabolizing enzyme (SmNACE), a receptor enzyme suspected to be involved in immune evasion by the parasite at the adult stage. Docking of commercial libraries into a homology model of the enzyme has led to the discovery of two in vitro micromolar inhibitors. Further structure–activity relationship studies have allowed a 3-log gain in potency, accompanied by a largely enhanced selectivity for the parasitic enzyme over the human homologue CD38.

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Koniev, O., and Wagner, A.

Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation, Chem. Soc. Rev., 2015, 44, 5495-5551.

Bioconjugation methodologies have proven to play a central enabling role in the recent development of biotherapeutics and chemical biology approaches. Recent endeavours in these fields shed light on unprecedented chemical challenges to attain bioselectivity, biocompatibility, and biostability required by modern applications. In this review the current developments in various techniques of selective bond forming reactions of proteins and peptides were highlighted. The utility of each endogenous amino acid-selective conjugation methodology in the fields of biology and protein science has been surveyed with emphasis on the most relevant among reported transformations; selectivity and practical use have been discussed.

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Neuberg, P., Périno, A., Morin-Picardat, E., Anton, N., Darwich, Z., Weltin, D., Mely, Y., Klymchenko, A. S., Remy, JS., and Wagner, A.

Photopolymerized micelles of diacetylene amphiphile: physical characterization and cell delivery properties, Chem. Commun., 2015, 51, 11595-11598.

A series of polydiacetylene (PDA) – based micelles were prepared from diacetylenic surfactant bearing polyethylene glycol, by increasing UV-irradiation times. These polymeric lipid micelles were analyzed by physicochemical methods, electron microscopy and NMR analysis. Cellular delivery of fluorescent dye suggests that adjusting the polymerization state is vital to reach the full in vitro potential of PDA-based delivery systems.

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Leriche, G., Jacques, S. A., Nothisen, M., Baumlin, N., Muller, C. D., Bagnard, D., Remy, JS., and Wagner, A.

Spiro di-orthoester (SpiDo), a human plasma stable acid-sensitive cleavable linker for lysosomal release, Bioconjugate Chem., 2015, 26, 1461-1465.

pH-sensitive linkers designed to undergo selective hydrolysis at acidic pH compared to physiological pH can be used for selective release of therapeutics selectively at targets and orthoesters have been demonstrated to be good candidates for such linkers. Following an HPLC screening, a Spiro Diorthoester (SpiDo) derivative was identified as a potent acid-labile group for the development of pH-sensitive targeted systems. After incorporation of this linker into activatable FRET-based probe and side-by-side comparison to a well-known alkylhydrazone linker, this SpiDo linker has shown a fast and pH sensitive hydrolysis for mild acidic conditions, a pH sensitive lysosomal hydrolysis, and high stability in human plasma.

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Koniev, O., Kolodych, S., Baatarkhuu, Z., Bonnefoy, JY., and Wagner, A.

MAPN: first-in-class reagent for kinetically resolved thiol-to-thiol conjugation, Bioconjugate Chem., 2015, 26, 1863–1867.

Amine-to-thiol coupling is the most common route for the preparation of antibody–drug conjugates (ADC). It is usually achieved by using heterobifunctional reagents possessing an activated ester at one end and a maleimide group at the other. However, maleimide-based conjugates were recently revealed to have limited stability in blood circulation, which can compromise therapeutic efficacy of the conjugate. To address this issue, we have developed a heterobifunctional reagent, sodium 4-((4-(cyanoethynyl)benzoyl)oxy)-2,3,5,6-tetrafluorobenzenesulfonate (CBTF), for amine-to-thiol coupling. It comprises a recently described 3-arylpropionitrile (APN) function in replacement of maleimide and allows for the preparation of remarkably stable conjugates. A series of antibody–dye conjugates have been prepared using this reagent and shown superior stability in human blood plasma compared to maleimide-derived conjugates.

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Flacher, V., Neuberg, P., Point, F., Daubeuf, F., Muller, Q., Sigwalt, D., Fauny, J. D., Remy, JS., Frossard, N., Wagner, A., Mueller, C. G., and Schaeffer, E.

Mannoside glycolipid conjugates display anti-inflammatory activity by inhibition of toll-like receptor-4 mediated cell activation, ACS Chem. Biol., 2015, 10, 2697–2705.

Inhibition of excessive Toll-like receptor 4 (TLR4) signaling is a therapeutic approach pursued for many inflammatory diseases. We report that Mannoside Glycolipid Conjugates (MGCs) selectively blocked TLR4-mediated activation of human monocytes and monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS). They potently suppressed pro-inflammatory cytokine secretion and maturation of DCs exposed to LPS, leading to impaired T cell stimulation. MGCs did not interfere with LPS and could act in a delayed manner, hours after LPS stimulation. Their inhibitory action required both the sugar heads and the lipid chain, although the nature of the sugar and the structure of the lipid tail could be modified. They blocked early signaling events at the cell membrane, enhanced internalization of CD14 receptors, and prevented colocalization of CD14 and TLR4, thereby abolishing NF-κB nuclear translocation. When the best lead conjugate was tested in a mouse model of LPS-induced acute lung inflammation, it displayed an anti-inflammatory action by suppressing the recruitment of neutrophils. Thus, MGCs could serve as promising leads for the development of selective TLR4 antagonistic agents for inflammatory diseases.

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