You will find below the list of publications of all the members of the Peptides, Glycoconjugates and Metals in Biology research pole. For individual or theme-specific publications, please consult the research or the personal pages via the members list using the sidebar navigation tool.
2017 |
R de Oliveira; M Durand; L Challier; P Messina; J M Swiecicki; M Di Pisa; G Chassaing; S Lavielle; O Buriez; E Labbé Journal of Electroanalytical Chemistry, 788 , p. 225–231, 2017. @article{deOliveira:2017, title = {Electrochemical quenching of the fluorescence produced by NBD-labelled cell penetrating peptides: A contribution to the study of their internalization in large unilamellar vesicles}, author = {R de Oliveira and M Durand and L Challier and P Messina and J M Swiecicki and M Di Pisa and G Chassaing and S Lavielle and O Buriez and E Labb\'{e}}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85013176758&doi=10.1016%2fj.jelechem.2017.02.006&partnerID=40&md5=725e8c07b1f4090ecf4f2ceabb57e6f7}, doi = {10.1016/j.jelechem.2017.02.006}, year = {2017}, date = {2017-01-01}, journal = {Journal of Electroanalytical Chemistry}, volume = {788}, pages = {225--231}, abstract = {This work investigates the implementation of a simple and versatile electrochemical setup aimed at achieving a fast and complete fluorescence extinction of NBD-labelled (NBD = 7-nitrobenz-2-oxa-1,3-diazole) cell penetrating peptides contained in 2\textendash5 cm3 samples containing phosphate buffer + large unilamellar vesicles. The quenching is obtained through a reductive electrolysis in a 2-compartment cell homebuilt from disposable plastic labware, which remains inert towards the adsorption of both peptides and lipid vesicles. Considering the micromolar concentration of NBD-tagged peptides, the main electrochemical reaction observed is hydrogen evolution, NBD reduction representing a small fraction of the cathodic current/charge engaged. The electrolysis conditions are discussed with respect to the nature of the reduction products formed, the integrity of large unilamellar vesicles and phosphate buffering properties. This electrochemical method is compared to the traditional chemical dithionite quenching of NBD and tested to monitor the internalization of cell penetrating peptides in large unilamellar vesicles. © 2017 Elsevier B.V.}, keywords = {}, pubstate = {published}, tppubtype = {article} } This work investigates the implementation of a simple and versatile electrochemical setup aimed at achieving a fast and complete fluorescence extinction of NBD-labelled (NBD = 7-nitrobenz-2-oxa-1,3-diazole) cell penetrating peptides contained in 2–5 cm3 samples containing phosphate buffer + large unilamellar vesicles. The quenching is obtained through a reductive electrolysis in a 2-compartment cell homebuilt from disposable plastic labware, which remains inert towards the adsorption of both peptides and lipid vesicles. Considering the micromolar concentration of NBD-tagged peptides, the main electrochemical reaction observed is hydrogen evolution, NBD reduction representing a small fraction of the cathodic current/charge engaged. The electrolysis conditions are discussed with respect to the nature of the reduction products formed, the integrity of large unilamellar vesicles and phosphate buffering properties. This electrochemical method is compared to the traditional chemical dithionite quenching of NBD and tested to monitor the internalization of cell penetrating peptides in large unilamellar vesicles. © 2017 Elsevier B.V. |
Identification of the Tau phosphorylation pattern that drives its aggregation Article de journal C Despres; C Byrne; H Qi; F -X Cantrelle; I Huvent; B Chambraud; E -E Baulieu; Y Jacquot; I Landrieu; G Lippens; C Smet-Nocca Proceedings of the National Academy of Sciences of the United States of America, 114 (34), p. 9080–9085, 2017. @article{Despres:2017, title = {Identification of the Tau phosphorylation pattern that drives its aggregation}, author = {C Despres and C Byrne and H Qi and F -X Cantrelle and I Huvent and B Chambraud and E -E Baulieu and Y Jacquot and I Landrieu and G Lippens and C Smet-Nocca}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027866366&doi=10.1073%2fpnas.1708448114&partnerID=40&md5=54e7f2c753bbd1b2171962fa9cf74fde}, doi = {10.1073/pnas.1708448114}, year = {2017}, date = {2017-01-01}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {114}, number = {34}, pages = {9080--9085}, abstract = {Determining the functional relationship between Tau phosphorylation and aggregation has proven a challenge owing to the multiple potential phosphorylation sites and their clustering in the Tau sequence. We use here in vitro kinase assays combined with NMR spectroscopy as an analytical tool to generate well-characterized phosphorylated Tau samples and show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 site, yields a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy. On the basis of conformational analysis of synthetic phosphorylated peptides, we show that aggregation of the samples correlates with destabilization of the turn-like structure defined by phosphorylation of Ser202/Thr205. © 2017, National Academy of Sciences. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Determining the functional relationship between Tau phosphorylation and aggregation has proven a challenge owing to the multiple potential phosphorylation sites and their clustering in the Tau sequence. We use here in vitro kinase assays combined with NMR spectroscopy as an analytical tool to generate well-characterized phosphorylated Tau samples and show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 site, yields a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy. On the basis of conformational analysis of synthetic phosphorylated peptides, we show that aggregation of the samples correlates with destabilization of the turn-like structure defined by phosphorylation of Ser202/Thr205. © 2017, National Academy of Sciences. All rights reserved. |
ERα dimerization: a key factor for the weak estrogenic activity of an ERα modulator unable to compete with estradiol in binding assays Article de journal G Leclercq; I Laïos; C Elie-Caille; D Leiber; G Laurent; E Lesniewska; Z Tanfin; Y Jacquot Journal of Receptors and Signal Transduction, 37 (2), p. 149–166, 2017. @article{Leclercq:2017, title = {ERα dimerization: a key factor for the weak estrogenic activity of an ERα modulator unable to compete with estradiol in binding assays}, author = {G Leclercq and I La\"{i}os and C Elie-Caille and D Leiber and G Laurent and E Lesniewska and Z Tanfin and Y Jacquot}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84978160581&doi=10.1080%2f10799893.2016.1203940&partnerID=40&md5=5ed36d16cd7bed348ed361de9fc2db49}, doi = {10.1080/10799893.2016.1203940}, year = {2017}, date = {2017-01-01}, journal = {Journal of Receptors and Signal Transduction}, volume = {37}, number = {2}, pages = {149--166}, abstract = {Estrothiazine (ESTZ) is a weak estrogen sharing structural similarities with coumestrol. ESTZ failed to compete with [3H]17β-estradiol ([3H]17β-E2) for binding to the estrogen receptor α (ERα), questioning its ability to interact with the receptor. However, detection by atomic force spectroscopy (AFS) of an ESTZ-induced ERα dimerization has eliminated any remaining doubts. The effect of the compound on the proliferation of ERα-positive and negative breast cancer cells confirmed the requirement of the receptor. The efficiency of ESTZ in MCF-7 cells was weak without any potency to modify the proliferation profile of estradiol and coumestrol. Growth enhancement was associated with a proteasomal degradation of ERα without substantial recruitment of LxxLL coactivators. This may be related to an unusual delay between the acquisition by the receptor of an ERE-binding capacity and the subsequent estrogen-dependent transcription. A complementary ability to enhance TPA-induced AP-1 transcription was observed, even at concentrations insufficient to activate the ERα, suggesting a partly independent mechanism. ESTZ also rapidly and transiently activated ERK1/2 likely through membrane estrogenic pathways provoking a reorganization of the actin network. Finally, the systematic absence of biological responses with an ESTZ derivative unable to induce ERα dimerization stresses the importance of this step in the action of the compound, as reported for conventional estrogens. In view of the existence of many other ERα modulators (endocrine disruptors such as, for example, pesticides, environmental contaminants or phytoestrogens) with extremely weak or similar apparent lack of binding ability, our work may appear as pilot investigation for assessing their mechanism of action. © 2016 Informa UK Limited, trading as Taylor & Francis Group.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Estrothiazine (ESTZ) is a weak estrogen sharing structural similarities with coumestrol. ESTZ failed to compete with [3H]17β-estradiol ([3H]17β-E2) for binding to the estrogen receptor α (ERα), questioning its ability to interact with the receptor. However, detection by atomic force spectroscopy (AFS) of an ESTZ-induced ERα dimerization has eliminated any remaining doubts. The effect of the compound on the proliferation of ERα-positive and negative breast cancer cells confirmed the requirement of the receptor. The efficiency of ESTZ in MCF-7 cells was weak without any potency to modify the proliferation profile of estradiol and coumestrol. Growth enhancement was associated with a proteasomal degradation of ERα without substantial recruitment of LxxLL coactivators. This may be related to an unusual delay between the acquisition by the receptor of an ERE-binding capacity and the subsequent estrogen-dependent transcription. A complementary ability to enhance TPA-induced AP-1 transcription was observed, even at concentrations insufficient to activate the ERα, suggesting a partly independent mechanism. ESTZ also rapidly and transiently activated ERK1/2 likely through membrane estrogenic pathways provoking a reorganization of the actin network. Finally, the systematic absence of biological responses with an ESTZ derivative unable to induce ERα dimerization stresses the importance of this step in the action of the compound, as reported for conventional estrogens. In view of the existence of many other ERα modulators (endocrine disruptors such as, for example, pesticides, environmental contaminants or phytoestrogens) with extremely weak or similar apparent lack of binding ability, our work may appear as pilot investigation for assessing their mechanism of action. © 2016 Informa UK Limited, trading as Taylor & Francis Group. |
Y Jacquot; D Spaggiari; J Schappler; E Lesniewska; S Rudaz; G Leclercq European Journal of Pharmaceutical Sciences, 109 , p. 169–181, 2017. @article{Jacquot:2017, title = {ERE-dependent transcription and cell proliferation: Independency of these two processes mediated by the introduction of a sulfone function into the weak estrogen estrothiazine}, author = {Y Jacquot and D Spaggiari and J Schappler and E Lesniewska and S Rudaz and G Leclercq}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028007094&doi=10.1016%2fj.ejps.2017.07.026&partnerID=40&md5=f0d8a84c9a0461377a0a813ab7bd745c}, doi = {10.1016/j.ejps.2017.07.026}, year = {2017}, date = {2017-01-01}, journal = {European Journal of Pharmaceutical Sciences}, volume = {109}, pages = {169--181}, abstract = {The synthetic coumestrol derivative 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one (estrothiazine, ESTZ) has been identified as a weak estrogen receptor α (ERα) ligand unable to compete with tritiated estradiol. The biological activity of this compound, supported by a methoxy group in position 3, seems mainly to result from its capacity to activate ERα dimerization without any participation of coactivators. In support of this view and referring to conventional estrogens, an ESTZ metabolism study conducted with hepatic human microsomes failed to provide any argument in favour of an estrogenic activity dependent on a metabolic conversion of the compound into hydroxylated metabolites with strong receptor activation ability. Interestingly, we failed to detect any oxidation of the sulfur atom of the compound. In the light of pharmacological literature data concerning sulfonylation, we assessed ERα-mediated activities generated by two sulfonylated ESTZ derivatives in which the methoxy group that plays a key role in its mechanism of action was maintained or removed. Sulfonylated ESTZ, even in its demethoxylated form, induced ERE-mediated transcriptions in MCF-7 breast cancer cells, without affecting the ERα turnover rate. In contrast to ESTZ, this compound failed to enhance the proliferation of ERα-positive breast cancer cells, suggesting that its sulfone function confers upon the receptor a capacity to elicit some of the known characteristics associated with estrogenic responses. Moreover, we demonstrated that this sulfone may contribute to ERα dimerization without any requirement of the methoxy group. Nevertheless, it seems to cooperate with this group, as reflected by a weak ability of the sulfonylated form of ESTZ to compete with tritiated estradiol for ERα-binding. Assessment of the docking of this compound within the ligand-binding domain of the receptor by molecular dynamics provided an explanation for this observation since the sulfone is engulfed in a small hydrophobic pocket involving the residues Leu-346, Leu-349, Ala-350 and Leu-384, also known to recruit coactivators. This work not only reports the sulfone functional group as a pharmacophore for estrogenic activity, but also opens new perspectives for the development of estrogenic molecules with therapeutic purpose and devoid of proliferative side effects. © 2017 Elsevier B.V.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The synthetic coumestrol derivative 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one (estrothiazine, ESTZ) has been identified as a weak estrogen receptor α (ERα) ligand unable to compete with tritiated estradiol. The biological activity of this compound, supported by a methoxy group in position 3, seems mainly to result from its capacity to activate ERα dimerization without any participation of coactivators. In support of this view and referring to conventional estrogens, an ESTZ metabolism study conducted with hepatic human microsomes failed to provide any argument in favour of an estrogenic activity dependent on a metabolic conversion of the compound into hydroxylated metabolites with strong receptor activation ability. Interestingly, we failed to detect any oxidation of the sulfur atom of the compound. In the light of pharmacological literature data concerning sulfonylation, we assessed ERα-mediated activities generated by two sulfonylated ESTZ derivatives in which the methoxy group that plays a key role in its mechanism of action was maintained or removed. Sulfonylated ESTZ, even in its demethoxylated form, induced ERE-mediated transcriptions in MCF-7 breast cancer cells, without affecting the ERα turnover rate. In contrast to ESTZ, this compound failed to enhance the proliferation of ERα-positive breast cancer cells, suggesting that its sulfone function confers upon the receptor a capacity to elicit some of the known characteristics associated with estrogenic responses. Moreover, we demonstrated that this sulfone may contribute to ERα dimerization without any requirement of the methoxy group. Nevertheless, it seems to cooperate with this group, as reflected by a weak ability of the sulfonylated form of ESTZ to compete with tritiated estradiol for ERα-binding. Assessment of the docking of this compound within the ligand-binding domain of the receptor by molecular dynamics provided an explanation for this observation since the sulfone is engulfed in a small hydrophobic pocket involving the residues Leu-346, Leu-349, Ala-350 and Leu-384, also known to recruit coactivators. This work not only reports the sulfone functional group as a pharmacophore for estrogenic activity, but also opens new perspectives for the development of estrogenic molecules with therapeutic purpose and devoid of proliferative side effects. © 2017 Elsevier B.V. |
Exploiting Benzophenone Photoreactivity To Probe the Phospholipid Environment and Insertion Depth of the Cell-Penetrating Peptide Penetratin in Model Membranes Article de journal C -Y Jiao; E Sachon; I D Alves; G Chassaing; G Bolbach; S Sagan Angewandte Chemie - International Edition, 56 (28), p. 8226–8230, 2017. @article{Jiao:2017, title = {Exploiting Benzophenone Photoreactivity To Probe the Phospholipid Environment and Insertion Depth of the Cell-Penetrating Peptide Penetratin in Model Membranes}, author = {C -Y Jiao and E Sachon and I D Alves and G Chassaing and G Bolbach and S Sagan}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021264790&doi=10.1002%2fanie.201703465&partnerID=40&md5=27efd27206b0847481f97a36b451b7a1}, doi = {10.1002/anie.201703465}, year = {2017}, date = {2017-01-01}, journal = {Angewandte Chemie - International Edition}, volume = {56}, number = {28}, pages = {8226--8230}, abstract = {Penetratin (RQIKIWFQNRRMKWKK) enters cells by different mechanisms, including membrane translocation, thus implying that the peptide interacts with the lipid bilayer. Penetratin also crosses the membrane of artificial vesicles, depending on their phospholipid content. To evaluate the phospholipid preference of penetratin, as the first step of translocation, we exploited the benzophenone triplet kinetics of hydrogen abstraction, which is slower for secondary than for allylic hydrogen atoms. By using multilamellar vesicles of varying phospholipid content, we identified and characterized the cross-linked products by MALDI-TOF mass spectrometry. Penetratin showed a preference for negatively charged (vs. zwitterionic) polar heads, and for unsaturated (vs. saturated) and short (vs. long) saturated phospholipids. Our study highlights the potential of using benzophenone to probe the environment and insertion depth of membranotropic peptides in membranes. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } Penetratin (RQIKIWFQNRRMKWKK) enters cells by different mechanisms, including membrane translocation, thus implying that the peptide interacts with the lipid bilayer. Penetratin also crosses the membrane of artificial vesicles, depending on their phospholipid content. To evaluate the phospholipid preference of penetratin, as the first step of translocation, we exploited the benzophenone triplet kinetics of hydrogen abstraction, which is slower for secondary than for allylic hydrogen atoms. By using multilamellar vesicles of varying phospholipid content, we identified and characterized the cross-linked products by MALDI-TOF mass spectrometry. Penetratin showed a preference for negatively charged (vs. zwitterionic) polar heads, and for unsaturated (vs. saturated) and short (vs. long) saturated phospholipids. Our study highlights the potential of using benzophenone to probe the environment and insertion depth of membranotropic peptides in membranes. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim |
Synthesis of Homoditopic Ligands with an Incrementable Rodlike Backbone Article de journal P Demay-Drouhard; L -M Chamoreau; R Guillot; C Policar; H C Bertrand European Journal of Organic Chemistry, 2017 (1), p. 131–137, 2017. @article{Demay-Drouhard:2017, title = {Synthesis of Homoditopic Ligands with an Incrementable Rodlike Backbone}, author = {P Demay-Drouhard and L -M Chamoreau and R Guillot and C Policar and H C Bertrand}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85007178925&doi=10.1002%2fejoc.201601081&partnerID=40&md5=4e3e60591df3842d6c169cf43161de0f}, doi = {10.1002/ejoc.201601081}, year = {2017}, date = {2017-01-01}, journal = {European Journal of Organic Chemistry}, volume = {2017}, number = {1}, pages = {131--137}, abstract = {We describe the synthesis of architectures that consist of a symmetrical rodlike oligo(phenylene-ethynylene) (OPE) backbone of incrementable length connected to a pair of classical ligands for metal coordination. OPE spacers decorated with various end groups and incorporating up to seven phenylene-acetylene repeat units were quickly obtained through a bidirectional approach. Efficient further functionalization with useful coordinating groups were achieved. The resulting homoditopic platforms are of interest in numerous fields ranging from supramolecular chemistry to materials science. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } We describe the synthesis of architectures that consist of a symmetrical rodlike oligo(phenylene-ethynylene) (OPE) backbone of incrementable length connected to a pair of classical ligands for metal coordination. OPE spacers decorated with various end groups and incorporating up to seven phenylene-acetylene repeat units were quickly obtained through a bidirectional approach. Efficient further functionalization with useful coordinating groups were achieved. The resulting homoditopic platforms are of interest in numerous fields ranging from supramolecular chemistry to materials science. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim |
Rhenium Complexes Based on 2-Pyridyl-1,2,3-triazole Ligands: A New Class of CO2 Reduction Catalysts Article de journal H Y V Ching; X Wang; M He; N Perujo Holland; R Guillot; C Slim; S Griveau; H C Bertrand; C Policar; F Bedioui; M Fontecave Inorganic Chemistry, 56 (5), p. 2966–2976, 2017. @article{Ching:2017, title = {Rhenium Complexes Based on 2-Pyridyl-1,2,3-triazole Ligands: A New Class of CO2 Reduction Catalysts}, author = {H Y V Ching and X Wang and M He and N Perujo Holland and R Guillot and C Slim and S Griveau and H C Bertrand and C Policar and F Bedioui and M Fontecave}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85014526293&doi=10.1021%2facs.inorgchem.6b03078&partnerID=40&md5=5aa6a6db21554e7bca56e0f1e1de9856}, doi = {10.1021/acs.inorgchem.6b03078}, year = {2017}, date = {2017-01-01}, journal = {Inorganic Chemistry}, volume = {56}, number = {5}, pages = {2966--2976}, abstract = {A series of [Re(NtextasciicircumN)(CO)3(X)] (NtextasciicircumN = diimine and X = halide) complexes based on 4-(2-pyridyl)-1,2,3-triazole (pyta) and 1-(2-pyridyl)-1,2,3-triazole (tapy) diimine ligands have been prepared and electrochemically characterized. The first ligand-based reduction process is shown to be highly sensitive to the nature of the isomer as well as to the substituents on the pyridyl ring, with the peak potential changing by up to 700 mV. The abilities of this class of complexes to catalyze the electroreduction and photoreduction of CO2 were assessed for the first time. It is found that only Re pyta complexes that have a first reduction wave with a peak potential at ca. −1.7 V vs SCE are active, producing CO as the major product, together with small amounts of H2 and formic acid. The catalytic wave that is observed in the CVs is enhanced by the addition of water or trifluoroethanol as a proton source. Long-term controlled potential electrolysis experiments gave total Faradaic yield close to 100%. In particular, functionalization of the triazolyl ring with a 2,4,6-tri-tert-butylphenyl group provided the catalyst with a remarkable stability. © 2017 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A series of [Re(NtextasciicircumN)(CO)3(X)] (NtextasciicircumN = diimine and X = halide) complexes based on 4-(2-pyridyl)-1,2,3-triazole (pyta) and 1-(2-pyridyl)-1,2,3-triazole (tapy) diimine ligands have been prepared and electrochemically characterized. The first ligand-based reduction process is shown to be highly sensitive to the nature of the isomer as well as to the substituents on the pyridyl ring, with the peak potential changing by up to 700 mV. The abilities of this class of complexes to catalyze the electroreduction and photoreduction of CO2 were assessed for the first time. It is found that only Re pyta complexes that have a first reduction wave with a peak potential at ca. −1.7 V vs SCE are active, producing CO as the major product, together with small amounts of H2 and formic acid. The catalytic wave that is observed in the CVs is enhanced by the addition of water or trifluoroethanol as a proton source. Long-term controlled potential electrolysis experiments gave total Faradaic yield close to 100%. In particular, functionalization of the triazolyl ring with a 2,4,6-tri-tert-butylphenyl group provided the catalyst with a remarkable stability. © 2017 American Chemical Society. |
Re(I) carbonyl complexes: Multimodal platforms for inorganic chemical biology Article de journal S Hostachy; C Policar; N Delsuc Coordination Chemistry Reviews, 351 , p. 172–188, 2017. @article{Hostachy:2017, title = {Re(I) carbonyl complexes: Multimodal platforms for inorganic chemical biology}, author = {S Hostachy and C Policar and N Delsuc}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85020033654&doi=10.1016%2fj.ccr.2017.05.004&partnerID=40&md5=ea1241c6f9199448b3fbb2bfc259b363}, doi = {10.1016/j.ccr.2017.05.004}, year = {2017}, date = {2017-01-01}, journal = {Coordination Chemistry Reviews}, volume = {351}, pages = {172--188}, abstract = {Bio-imaging, by enabling the visualization of biomolecules of interest, has proved to be highly informative in the study of biological processes. Although fluorescence microscopy is probably one of the most used techniques, alternative methods of imaging, providing complementary information, are emerging. In this context, metal complexes represent valuable platforms for multimodal imaging, since they may combine interesting spectroscopic features and biologically relevant functionalization on a single molecular core. In particular, d6 low-spin rhenium tri-carbonyl complexes display unique luminescence and vibrational properties, and can be readily functionalized. Here we review their applications and potential as probes or drugs relying on their photophysical properties, before focusing on their use as multimodal probes for the labelling and imaging of peptides and proteins. © 2017 Elsevier B.V.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Bio-imaging, by enabling the visualization of biomolecules of interest, has proved to be highly informative in the study of biological processes. Although fluorescence microscopy is probably one of the most used techniques, alternative methods of imaging, providing complementary information, are emerging. In this context, metal complexes represent valuable platforms for multimodal imaging, since they may combine interesting spectroscopic features and biologically relevant functionalization on a single molecular core. In particular, d6 low-spin rhenium tri-carbonyl complexes display unique luminescence and vibrational properties, and can be readily functionalized. Here we review their applications and potential as probes or drugs relying on their photophysical properties, before focusing on their use as multimodal probes for the labelling and imaging of peptides and proteins. © 2017 Elsevier B.V. |
E Mathieu; A -S Bernard; N Delsuc; E Quévrain; G Gazzah; B Lai; F Chain; P Langella; M Bachelet; J Masliah; P Seksik; C Policar Inorganic Chemistry, 56 (5), p. 2545–2555, 2017. @article{Mathieu:2017, title = {A Cell-Penetrant Manganese Superoxide Dismutase (MnSOD) Mimic Is Able to Complement MnSOD and Exerts an Antiinflammatory Effect on Cellular and Animal Models of Inflammatory Bowel Diseases}, author = {E Mathieu and A -S Bernard and N Delsuc and E Qu\'{e}vrain and G Gazzah and B Lai and F Chain and P Langella and M Bachelet and J Masliah and P Seksik and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85014763334&doi=10.1021%2facs.inorgchem.6b02695&partnerID=40&md5=acd51065ea36d5da707ec8c1915634a0}, doi = {10.1021/acs.inorgchem.6b02695}, year = {2017}, date = {2017-01-01}, journal = {Inorganic Chemistry}, volume = {56}, number = {5}, pages = {2545--2555}, abstract = {Inorganic complexes are increasingly used for biological and medicinal applications, and the question of the cell penetration and distribution of metallodrugs is key to understanding their biological activity. Oxidative stress is known to be involved in inflammation and in inflammatory bowel diseases for which antioxidative defenses are weakened. We report here the study of the manganese complex Mn1 mimicking superoxide dismutase (SOD), a protein involved in cell protection against oxidative stress, using an approach in inorganic cellular chemistry combining the investigation of Mn1 intracellular speciation using mass spectrometry and of its quantification and distribution using electron paramagnetic resonance and spatially resolved X-ray fluorescence with evaluation of its biological activity. More precisely, we have looked for and found the MS signature of Mn1 in cell lysates and quantified the overall manganese content. Intestinal epithelial cells activated by bacterial lipopolysaccharide were taken as a cellular model of oxidative stress and inflammation. DNBS-induced colitis in mice was used to investigate Mn1 activity in vivo. Mn1 exerts an intracellular antiinflammatory activity, remains at least partially coordinated, with diffuse distribution over the whole cell, and functionally complements mitochondrial MnSOD. © 2017 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Inorganic complexes are increasingly used for biological and medicinal applications, and the question of the cell penetration and distribution of metallodrugs is key to understanding their biological activity. Oxidative stress is known to be involved in inflammation and in inflammatory bowel diseases for which antioxidative defenses are weakened. We report here the study of the manganese complex Mn1 mimicking superoxide dismutase (SOD), a protein involved in cell protection against oxidative stress, using an approach in inorganic cellular chemistry combining the investigation of Mn1 intracellular speciation using mass spectrometry and of its quantification and distribution using electron paramagnetic resonance and spatially resolved X-ray fluorescence with evaluation of its biological activity. More precisely, we have looked for and found the MS signature of Mn1 in cell lysates and quantified the overall manganese content. Intestinal epithelial cells activated by bacterial lipopolysaccharide were taken as a cellular model of oxidative stress and inflammation. DNBS-induced colitis in mice was used to investigate Mn1 activity in vivo. Mn1 exerts an intracellular antiinflammatory activity, remains at least partially coordinated, with diffuse distribution over the whole cell, and functionally complements mitochondrial MnSOD. © 2017 American Chemical Society. |
Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption Article de journal R Charif; C Granotier-Beckers; H C Bertrand; J Poupon; E Ségal-Bendirdjian; M -P Teulade-Fichou; F D Boussin; S Bombard Chemical Research in Toxicology, 30 (8), p. 1629–1640, 2017. @article{Charif:2017, title = {Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption}, author = {R Charif and C Granotier-Beckers and H C Bertrand and J Poupon and E S\'{e}gal-Bendirdjian and M -P Teulade-Fichou and F D Boussin and S Bombard}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027852578&doi=10.1021%2facs.chemrestox.7b00131&partnerID=40&md5=fd5e6afe1b7d7488cd33597bef254e71}, doi = {10.1021/acs.chemrestox.7b00131}, year = {2017}, date = {2017-01-01}, journal = {Chemical Research in Toxicology}, volume = {30}, number = {8}, pages = {1629--1640}, abstract = {Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ). Pt-MPQ promotes the displacement of two telomeric proteins (TRF2 and TRF1) from telomeres, as well as the formation of telomere damage and telomere sister losses, whereas the control compound MPQ does not. This suggests that the platinum moiety potentiates the targeting of the G-quadruplex ligand to telomeres, opening a new perspective for telomere biology and anticancer therapy. Interestingly, the chemotherapy drug cisplatin, which has no specific affinity for G-quadruplex structures, partially induces the TRF2 delocalization from telomeres but produces less telomeric DNA damage, suggesting that this TRF2 displacement could be independent of G-quadruplex recognition. © 2017 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ). Pt-MPQ promotes the displacement of two telomeric proteins (TRF2 and TRF1) from telomeres, as well as the formation of telomere damage and telomere sister losses, whereas the control compound MPQ does not. This suggests that the platinum moiety potentiates the targeting of the G-quadruplex ligand to telomeres, opening a new perspective for telomere biology and anticancer therapy. Interestingly, the chemotherapy drug cisplatin, which has no specific affinity for G-quadruplex structures, partially induces the TRF2 delocalization from telomeres but produces less telomeric DNA damage, suggesting that this TRF2 displacement could be independent of G-quadruplex recognition. © 2017 American Chemical Society. |
Structure and Dynamics of an Intrinsically Disordered Protein Region That Partially Folds upon Binding by Chemical-Exchange NMR Article de journal C Charlier; G Bouvignies; P Pelupessy; A Walrant; R Marquant; M Kozlov; P De Ioannes; N Bolik-Coulon; S Sagan; P Cortes; A K Aggarwal; L Carlier; F Ferrage Journal of the American Chemical Society, 139 (35), p. 12219–12227, 2017. @article{Charlier:2017, title = {Structure and Dynamics of an Intrinsically Disordered Protein Region That Partially Folds upon Binding by Chemical-Exchange NMR}, author = {C Charlier and G Bouvignies and P Pelupessy and A Walrant and R Marquant and M Kozlov and P De Ioannes and N Bolik-Coulon and S Sagan and P Cortes and A K Aggarwal and L Carlier and F Ferrage}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028941202&doi=10.1021%2fjacs.7b05823&partnerID=40&md5=ce8846a9b03d31576ec301899a2c40f1}, doi = {10.1021/jacs.7b05823}, year = {2017}, date = {2017-01-01}, journal = {Journal of the American Chemical Society}, volume = {139}, number = {35}, pages = {12219--12227}, abstract = {Many intrinsically disordered proteins (IDPs) and protein regions (IDRs) engage in transient, yet specific, interactions with a variety of protein partners. Often, if not always, interactions with a protein partner lead to partial folding of the IDR. Characterizing the conformational space of such complexes is challenging: in solution-state NMR, signals of the IDR in the interacting region become broad, weak, and often invisible, while X-ray crystallography only provides information on fully ordered regions. There is thus a need for a simple method to characterize both fully and partially ordered regions in the bound state of IDPs. Here, we introduce an approach based on monitoring chemical exchange by NMR to investigate the state of an IDR that folds upon binding through the observation of the free state of the protein. Structural constraints for the bound state are obtained from chemical shifts, and site-specific dynamics of the bound state are characterized by relaxation rates. The conformation of the interacting part of the IDR was determined and subsequently docked onto the structure of the folded partner. We apply the method to investigate the interaction between the disordered C-terminal region of Artemis and the DNA binding domain of Ligase IV. We show that we can accurately reproduce the structure of the core of the complex determined by X-ray crystallography and identify a broader interface. The method is widely applicable to the biophysical investigation of complexes of disordered proteins and folded proteins. © 2017 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Many intrinsically disordered proteins (IDPs) and protein regions (IDRs) engage in transient, yet specific, interactions with a variety of protein partners. Often, if not always, interactions with a protein partner lead to partial folding of the IDR. Characterizing the conformational space of such complexes is challenging: in solution-state NMR, signals of the IDR in the interacting region become broad, weak, and often invisible, while X-ray crystallography only provides information on fully ordered regions. There is thus a need for a simple method to characterize both fully and partially ordered regions in the bound state of IDPs. Here, we introduce an approach based on monitoring chemical exchange by NMR to investigate the state of an IDR that folds upon binding through the observation of the free state of the protein. Structural constraints for the bound state are obtained from chemical shifts, and site-specific dynamics of the bound state are characterized by relaxation rates. The conformation of the interacting part of the IDR was determined and subsequently docked onto the structure of the folded partner. We apply the method to investigate the interaction between the disordered C-terminal region of Artemis and the DNA binding domain of Ligase IV. We show that we can accurately reproduce the structure of the core of the complex determined by X-ray crystallography and identify a broader interface. The method is widely applicable to the biophysical investigation of complexes of disordered proteins and folded proteins. © 2017 American Chemical Society. |
An All-in-One Molecule for the One-Step Synthesis of Functional Hybrid Silica Particles with Tunable Sizes Article de journal J Graffion; D Dems; M Demirelli; T Coradin; N Delsuc; C Aimé European Journal of Inorganic Chemistry, 2017 (43), p. 5047–5051, 2017. @article{Graffion:2017, title = {An All-in-One Molecule for the One-Step Synthesis of Functional Hybrid Silica Particles with Tunable Sizes}, author = {J Graffion and D Dems and M Demirelli and T Coradin and N Delsuc and C Aim\'{e}}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85035047611&doi=10.1002%2fejic.201701181&partnerID=40&md5=249333f958412776dc6966b033242102}, doi = {10.1002/ejic.201701181}, year = {2017}, date = {2017-01-01}, journal = {European Journal of Inorganic Chemistry}, volume = {2017}, number = {43}, pages = {5047--5051}, abstract = {Spherical particles with well-defined diameters were obtained by self-assembly of trityl-based molecules. Thanks to the robustness of the organic scaffold, a variety of modifications could be covalently introduced into the network so as to stabilize the supramolecular structure by a sol\textendashgel route. Using supramolecular chemistry, we showed that the synthesis of hybrid small molecules allowed engineering nanomaterials with tunable size and functionality. The use of a combination of different characterization techniques, including dynamic light scattering, cryoTEM, and solid-state NMR spectroscopy, provided careful understanding of the relationship between the molecular and supramolecular structures for further chemical engineering of supramolecular hybrid materials. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } Spherical particles with well-defined diameters were obtained by self-assembly of trityl-based molecules. Thanks to the robustness of the organic scaffold, a variety of modifications could be covalently introduced into the network so as to stabilize the supramolecular structure by a sol–gel route. Using supramolecular chemistry, we showed that the synthesis of hybrid small molecules allowed engineering nanomaterials with tunable size and functionality. The use of a combination of different characterization techniques, including dynamic light scattering, cryoTEM, and solid-state NMR spectroscopy, provided careful understanding of the relationship between the molecular and supramolecular structures for further chemical engineering of supramolecular hybrid materials. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim |
A host-guest system based on collagen-like triple-helix hybridization Article de journal N Delsuc; S Uchinomiya; A Ojida; I Hamachi Chemical Communications, 53 (51), p. 6856–6859, 2017. @article{Delsuc:2017, title = {A host-guest system based on collagen-like triple-helix hybridization}, author = {N Delsuc and S Uchinomiya and A Ojida and I Hamachi}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021764142&doi=10.1039%2fc7cc03055j&partnerID=40&md5=702ef29356b9c2adcdde22eeaaafb981}, doi = {10.1039/c7cc03055j}, year = {2017}, date = {2017-01-01}, journal = {Chemical Communications}, volume = {53}, number = {51}, pages = {6856--6859}, abstract = {A strategy inspired by tweezer receptors has been employed to develop a new host-guest system. The hybridization into a collagen-like triple helix is the driving force for the recognition that occurs with high affinity and selectivity. Several systems have been screened to find the best host-guest pair and this strategy may be implemented for tag fused protein recognition. © 2017 The Royal Society of Chemistry.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A strategy inspired by tweezer receptors has been employed to develop a new host-guest system. The hybridization into a collagen-like triple helix is the driving force for the recognition that occurs with high affinity and selectivity. Several systems have been screened to find the best host-guest pair and this strategy may be implemented for tag fused protein recognition. © 2017 The Royal Society of Chemistry. |
Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-Candida albicans Activity of Amphotericin B Using an Immunocompetent Murine Model Article de journal T Grisin; C Bories; M Bombardi; P M Loiseau; V Rouffiac; A Solgadi; J -M Mallet; G Ponchel; K Bouchemal Pharmaceutical Research, 34 (5), p. 1067–1082, 2017. @article{Grisin:2017, title = {Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-Candida albicans Activity of Amphotericin B Using an Immunocompetent Murine Model}, author = {T Grisin and C Bories and M Bombardi and P M Loiseau and V Rouffiac and A Solgadi and J -M Mallet and G Ponchel and K Bouchemal}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85011710508&doi=10.1007%2fs11095-017-2117-3&partnerID=40&md5=f9437388887f80d0478b2a95b7fd46ad}, doi = {10.1007/s11095-017-2117-3}, year = {2017}, date = {2017-01-01}, journal = {Pharmaceutical Research}, volume = {34}, number = {5}, pages = {1067--1082}, abstract = {Purpose: The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity. Methods: Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic® F127 20 wt% hydrogel. Results: The formulation completely cured C. albicans vaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC50 and the MIC90 decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI = 0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC. Conclusion: These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment. © 2017, Springer Science+Business Media New York.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Purpose: The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity. Methods: Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic® F127 20 wt% hydrogel. Results: The formulation completely cured C. albicans vaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC50 and the MIC90 decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI = 0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC. Conclusion: These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment. © 2017, Springer Science+Business Media New York. |
The inhibition of tyrosinase by some aryl butenes: A desired activity or a side effect to avoid Article de journal E Ketata; A Neifar; W Mihoubi; P Pigeon; H Gouzi; J -M Mallet; S Top; G K Gupta; G Jaouen; A Gargouri; M El Arbi Journal of Organometallic Chemistry, 848 , p. 133–141, 2017. @article{Ketata:2017, title = {The inhibition of tyrosinase by some aryl butenes: A desired activity or a side effect to avoid}, author = {E Ketata and A Neifar and W Mihoubi and P Pigeon and H Gouzi and J -M Mallet and S Top and G K Gupta and G Jaouen and A Gargouri and M El Arbi}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85026674207&doi=10.1016%2fj.jorganchem.2017.07.031&partnerID=40&md5=10c0783ea7acb8f6dbd54dbb19c427ca}, doi = {10.1016/j.jorganchem.2017.07.031}, year = {2017}, date = {2017-01-01}, journal = {Journal of Organometallic Chemistry}, volume = {848}, pages = {133--141}, abstract = {Inhibitory effects on the monophenolase activity of tyrosinase of some aryl butenes derivatives, having moderate to excellent inhibitory activity on MDA-MB-231 breast cancer cell, have been examined. The results show that the substitution of the phenol group by other functional moieties or its removal (unsubstituted phenyl) makes the loss of the tyrosinase inhibition effect of the compounds. Interestingly, the protection of the phenol group of the compounds by a sugar (glucose) led to the loss of the inhibitory activity on tyrosinase but maintained the antitumor activity. The tyrosinase inhibiting potential is considered as a side effect as it leads to depigmentation. Some ferrocenyl aryl butene compounds behave as reversible inhibitors of tyrosinase and kinetic analyses showed that the inhibition type of three derivatives compounds was competitive and another compound was non-competitive. Moreover, the compounds 8 and 19 were found to be the most potent inhibitors of tyrosinase activity among these compounds with IC50 values of 20 and 25 μM, respectively. However, compound 18 was the most effective compound against MDA-MB-231 tumoral cells with an IC50 value of 0.86 μM; it could be used as an anticancer drug without interfering with tyrosinase activity and pigmentation process. Conclusively, if some compounds are excellent candidates for cosmetics, others showed strong antitumor activity without depigmentation side effect. © 2017 Elsevier B.V.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Inhibitory effects on the monophenolase activity of tyrosinase of some aryl butenes derivatives, having moderate to excellent inhibitory activity on MDA-MB-231 breast cancer cell, have been examined. The results show that the substitution of the phenol group by other functional moieties or its removal (unsubstituted phenyl) makes the loss of the tyrosinase inhibition effect of the compounds. Interestingly, the protection of the phenol group of the compounds by a sugar (glucose) led to the loss of the inhibitory activity on tyrosinase but maintained the antitumor activity. The tyrosinase inhibiting potential is considered as a side effect as it leads to depigmentation. Some ferrocenyl aryl butene compounds behave as reversible inhibitors of tyrosinase and kinetic analyses showed that the inhibition type of three derivatives compounds was competitive and another compound was non-competitive. Moreover, the compounds 8 and 19 were found to be the most potent inhibitors of tyrosinase activity among these compounds with IC50 values of 20 and 25 μM, respectively. However, compound 18 was the most effective compound against MDA-MB-231 tumoral cells with an IC50 value of 0.86 μM; it could be used as an anticancer drug without interfering with tyrosinase activity and pigmentation process. Conclusively, if some compounds are excellent candidates for cosmetics, others showed strong antitumor activity without depigmentation side effect. © 2017 Elsevier B.V. |
Dimerization of the fungal defense lectin CCL2 is essential for its toxicity against nematodes Article de journal S Bleuler-Martinez; K Stutz; R Sieber; M Collot; J -M Mallet; M Hengartner; M Schubert; A Varrot; M Künzler Glycobiology, 27 (5), p. 486–500, 2017. @article{Bleuler-Martinez:2017, title = {Dimerization of the fungal defense lectin CCL2 is essential for its toxicity against nematodes}, author = {S Bleuler-Martinez and K Stutz and R Sieber and M Collot and J -M Mallet and M Hengartner and M Schubert and A Varrot and M K\"{u}nzler}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019108275&doi=10.1093%2fglycob%2fcww113&partnerID=40&md5=c1e6a86d1b5f5865f623bd1236f3fcbc}, doi = {10.1093/glycob/cww113}, year = {2017}, date = {2017-01-01}, journal = {Glycobiology}, volume = {27}, number = {5}, pages = {486--500}, abstract = {Lectins are used as defense effector proteins against predators, parasites and pathogens by animal, plant and fungal innate defense systems. These proteins bind to specific glycoepitopes on the cell surfaces and thereby interfere with the proper cellular functions of the various antagonists. The exact cellular toxicity mechanism is in many cases unclear. Lectin CCL2 of the mushroom Coprinopsis cinerea was previously shown to be toxic for Caenorhabditis elegans and Drosophila melanogaster. This toxicity is dependent on a single, high-affinity binding site for the trisaccharide GlcNAc(Fuca1,3)β1,4GlcNAc, which is a hallmark of nematode and insect N-glycan cores. The carbohydrate-binding site is located at an unusual position on the protein surface when compared to other β-trefoil lectins. Here, we show that CCL2 forms a compact dimer in solution and in crystals. Substitution of two amino acid residues at the dimer interface, R18A and F133A, interfered with dimerization of CCL2 and reduced toxicity but left carbohydrate-binding unaffected. These results, together with the positioning of the two carbohydrate-binding sites on the surface of the protein dimer, suggest that crosslinking of N-glycoproteins on the surface of intestinal cells of invertebrates is a crucial step in the mechanism of CCL2-mediated toxicity. Comparisons of the number and positioning of carbohydrate-binding sites among different dimerizing fungal β-trefoil lectins revealed a considerable variability in the carbohydrate-binding patterns of these proteins, which are likely to correlate with their respective functions. © 2016 The Author.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Lectins are used as defense effector proteins against predators, parasites and pathogens by animal, plant and fungal innate defense systems. These proteins bind to specific glycoepitopes on the cell surfaces and thereby interfere with the proper cellular functions of the various antagonists. The exact cellular toxicity mechanism is in many cases unclear. Lectin CCL2 of the mushroom Coprinopsis cinerea was previously shown to be toxic for Caenorhabditis elegans and Drosophila melanogaster. This toxicity is dependent on a single, high-affinity binding site for the trisaccharide GlcNAc(Fuca1,3)β1,4GlcNAc, which is a hallmark of nematode and insect N-glycan cores. The carbohydrate-binding site is located at an unusual position on the protein surface when compared to other β-trefoil lectins. Here, we show that CCL2 forms a compact dimer in solution and in crystals. Substitution of two amino acid residues at the dimer interface, R18A and F133A, interfered with dimerization of CCL2 and reduced toxicity but left carbohydrate-binding unaffected. These results, together with the positioning of the two carbohydrate-binding sites on the surface of the protein dimer, suggest that crosslinking of N-glycoproteins on the surface of intestinal cells of invertebrates is a crucial step in the mechanism of CCL2-mediated toxicity. Comparisons of the number and positioning of carbohydrate-binding sites among different dimerizing fungal β-trefoil lectins revealed a considerable variability in the carbohydrate-binding patterns of these proteins, which are likely to correlate with their respective functions. © 2016 The Author. |
A Secondary Structural Element in a Wide Range of Fucosylated Glycoepitopes Article de journal T Aeschbacher; M Zierke; M Smieško; M Collot; J -M Mallet; B Ernst; F H -T Allain; M Schubert Chemistry - A European Journal, 23 (48), p. 11598–11610, 2017. @article{Aeschbacher:2017, title = {A Secondary Structural Element in a Wide Range of Fucosylated Glycoepitopes}, author = {T Aeschbacher and M Zierke and M Smie\v{s}ko and M Collot and J -M Mallet and B Ernst and F H -T Allain and M Schubert}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85026659959&doi=10.1002%2fchem.201701866&partnerID=40&md5=7c128fcaf3c615a654962bafdbef76bc}, doi = {10.1002/chem.201701866}, year = {2017}, date = {2017-01-01}, journal = {Chemistry - A European Journal}, volume = {23}, number = {48}, pages = {11598--11610}, abstract = {The increasing understanding of the essential role of carbohydrates in development, and in a wide range of diseases fuels a rapidly growing interest in the basic principles governing carbohydrate-protein interactions. A still heavily debated issue regarding the recognition process is the degree of flexibility or rigidity of oligosaccharides. Combining NMR structure determination based on extensive experimental data with DFT and database searches, we have identified a set of trisaccharide motifs with a similar conformation that is characterized by a non-conventional C−H⋅⋅⋅O hydrogen bond. These motifs are present in numerous classes of oligosaccharides, found in everything from bacteria to mammals, including Lewis blood group antigens but also unusual motifs from amphibians and marine invertebrates. The set of trisaccharide motifs can be summarized with the consensus motifs X-β1,4-[Fucα1,3]-Y and X-β1,3-[Fucα1,4]-Y\textemdasha secondary structure we name [3,4]F-branch. The wide spectrum of possible modifications of this scaffold points toward a large variety of glycoepitopes, which nature generated using the same underlying architecture. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } The increasing understanding of the essential role of carbohydrates in development, and in a wide range of diseases fuels a rapidly growing interest in the basic principles governing carbohydrate-protein interactions. A still heavily debated issue regarding the recognition process is the degree of flexibility or rigidity of oligosaccharides. Combining NMR structure determination based on extensive experimental data with DFT and database searches, we have identified a set of trisaccharide motifs with a similar conformation that is characterized by a non-conventional C−H⋅⋅⋅O hydrogen bond. These motifs are present in numerous classes of oligosaccharides, found in everything from bacteria to mammals, including Lewis blood group antigens but also unusual motifs from amphibians and marine invertebrates. The set of trisaccharide motifs can be summarized with the consensus motifs X-β1,4-[Fucα1,3]-Y and X-β1,3-[Fucα1,4]-Y—a secondary structure we name [3,4]F-branch. The wide spectrum of possible modifications of this scaffold points toward a large variety of glycoepitopes, which nature generated using the same underlying architecture. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim |
Copper-Catalyzed Hydroamination of N-Allenylazoles: Access to Amino-Substituted N-Vinylazoles Article de journal L A Perego; R Blieck; J Michel; I Ciofini; L Grimaud; M Taillefer; F Monnier Advanced Synthesis and Catalysis, 359 (24), p. 4388–4392, 2017. @article{Perego:2017, title = {Copper-Catalyzed Hydroamination of N-Allenylazoles: Access to Amino-Substituted N-Vinylazoles}, author = {L A Perego and R Blieck and J Michel and I Ciofini and L Grimaud and M Taillefer and F Monnier}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85031504221&doi=10.1002%2fadsc.201700965&partnerID=40&md5=b6253215a708de34ef84f1990bc71129}, doi = {10.1002/adsc.201700965}, year = {2017}, date = {2017-01-01}, journal = {Advanced Synthesis and Catalysis}, volume = {359}, number = {24}, pages = {4388--4392}, abstract = {Building on mechanistic studies, the innate capability of azoles to act as a directing group has been exploited to design an efficient and simple procedure for the hydroamination of N-allenylazoles with secondary amines. The reaction proceeds under mild conditions by copper(I) catalysis yielding the corresponding original linear E allylic amines with total regio- and stereoselectivity. Density Functional Theory (DFT) calculations offer a mechanistic explanation of the significantly higher reactivity of N-allenyl-(1,2)-azoles compared to their 1,3-analogues as a result of the reaction-enhancing coordination of the pyridine-like nitrogen to the copper center. (Figure presented.). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } Building on mechanistic studies, the innate capability of azoles to act as a directing group has been exploited to design an efficient and simple procedure for the hydroamination of N-allenylazoles with secondary amines. The reaction proceeds under mild conditions by copper(I) catalysis yielding the corresponding original linear E allylic amines with total regio- and stereoselectivity. Density Functional Theory (DFT) calculations offer a mechanistic explanation of the significantly higher reactivity of N-allenyl-(1,2)-azoles compared to their 1,3-analogues as a result of the reaction-enhancing coordination of the pyridine-like nitrogen to the copper center. (Figure presented.). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim |
Copper-Catalyzed Hydroamination of Allenes: From Mechanistic Understanding to Methodology Development Article de journal L A Perego; R Blieck; A Groué; F Monnier; M Taillefer; I Ciofini; L Grimaud ACS Catalysis, 7 (7), p. 4253–4264, 2017. @article{Perego:2017a, title = {Copper-Catalyzed Hydroamination of Allenes: From Mechanistic Understanding to Methodology Development}, author = {L A Perego and R Blieck and A Grou\'{e} and F Monnier and M Taillefer and I Ciofini and L Grimaud}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85024925525&doi=10.1021%2facscatal.7b00911&partnerID=40&md5=5f3d3918b036996672327478a85efb5a}, doi = {10.1021/acscatal.7b00911}, year = {2017}, date = {2017-01-01}, journal = {ACS Catalysis}, volume = {7}, number = {7}, pages = {4253--4264}, abstract = {Experimental and theoretical mechanistic studies on the Cu(OTf)2-catalyzed hydroamination reaction of terminal allenes with secondary amines reveal that in situ generated cationic Cu(I) is the catalytically active species and explain the observed regio- and stereoselectivity for the unbranched E product. Insight into the structure of the relevant transition states allowed the generalization of this methodology to allenamides and N-allenylcarbamates under unprecedentedly mild and functional-group-tolerant conditions. Chelation effects by the amide oxygen in addition to electronic effects explain the high innate reactivity of this class of substrates. © 2017 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Experimental and theoretical mechanistic studies on the Cu(OTf)2-catalyzed hydroamination reaction of terminal allenes with secondary amines reveal that in situ generated cationic Cu(I) is the catalytically active species and explain the observed regio- and stereoselectivity for the unbranched E product. Insight into the structure of the relevant transition states allowed the generalization of this methodology to allenamides and N-allenylcarbamates under unprecedentedly mild and functional-group-tolerant conditions. Chelation effects by the amide oxygen in addition to electronic effects explain the high innate reactivity of this class of substrates. © 2017 American Chemical Society. |
A Dual Functional Electroactive and Fluorescent Probe for Coupled Measurements of Vesicular Exocytosis with High Spatial and Temporal Resolution Article de journal X Liu; A Savy; S Maurin; L Grimaud; F Darchen; D Quinton; E Labbé; O Buriez; J Delacotte; F Lemaître; M Guille-Collignon Angewandte Chemie - International Edition, 56 (9), p. 2366–2370, 2017. @article{Liu:2017a, title = {A Dual Functional Electroactive and Fluorescent Probe for Coupled Measurements of Vesicular Exocytosis with High Spatial and Temporal Resolution}, author = {X Liu and A Savy and S Maurin and L Grimaud and F Darchen and D Quinton and E Labb\'{e} and O Buriez and J Delacotte and F Lema\^{i}tre and M Guille-Collignon}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85010696856&doi=10.1002%2fanie.201611145&partnerID=40&md5=a51767157166d7f185f0195a28b347b8}, doi = {10.1002/anie.201611145}, year = {2017}, date = {2017-01-01}, journal = {Angewandte Chemie - International Edition}, volume = {56}, number = {9}, pages = {2366--2370}, abstract = {In this work, Fluorescent False Neurotransmitter 102 (FFN102), a synthesized analogue of biogenic neurotransmitters, was demonstrated to show both pH-dependent fluorescence and electroactivity. To study secretory behaviors at the single-vesicle level, FFN102 was employed as a new fluorescent/electroactive dual probe in a coupled technique (amperometry and total internal reflection fluorescence microscopy (TIRFM)). We used N13 cells, a stable clone of BON cells, to specifically accumulate FFN102 into their secretory vesicles, and then optical and electrochemical measurements of vesicular exocytosis were experimentally achieved by using indium tin oxide (ITO) transparent electrodes. Upon stimulation, FFN102 started to diffuse out from the acidic intravesicular microenvironment to the neutral extracellular space, leading to fluorescent emissions and to the electrochemical oxidation signals that were simultaneously collected from the ITO electrode surface. The correlation of fluorescence and amperometric signals resulting from the FFN102 probe allows real-time monitoring of single exocytotic events with both high spatial and temporal resolution. This work opens new possibilities in the investigation of exocytotic mechanisms. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } In this work, Fluorescent False Neurotransmitter 102 (FFN102), a synthesized analogue of biogenic neurotransmitters, was demonstrated to show both pH-dependent fluorescence and electroactivity. To study secretory behaviors at the single-vesicle level, FFN102 was employed as a new fluorescent/electroactive dual probe in a coupled technique (amperometry and total internal reflection fluorescence microscopy (TIRFM)). We used N13 cells, a stable clone of BON cells, to specifically accumulate FFN102 into their secretory vesicles, and then optical and electrochemical measurements of vesicular exocytosis were experimentally achieved by using indium tin oxide (ITO) transparent electrodes. Upon stimulation, FFN102 started to diffuse out from the acidic intravesicular microenvironment to the neutral extracellular space, leading to fluorescent emissions and to the electrochemical oxidation signals that were simultaneously collected from the ITO electrode surface. The correlation of fluorescence and amperometric signals resulting from the FFN102 probe allows real-time monitoring of single exocytotic events with both high spatial and temporal resolution. This work opens new possibilities in the investigation of exocytotic mechanisms. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim |
N-N bond formation in Ugi processes: from nitric acid to libraries of nitramines Article de journal V Mercalli; A Nyadanu; M Cordier; G C Tron; L Grimaud; L El Kaim Chemical Communications, 53 (13), p. 2118–2121, 2017. @article{Mercalli:2017, title = {N-N bond formation in Ugi processes: from nitric acid to libraries of nitramines}, author = {V Mercalli and A Nyadanu and M Cordier and G C Tron and L Grimaud and L El Kaim}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85012195472&doi=10.1039%2fc6cc10288c&partnerID=40&md5=74bc350d7ed83c98b00d926bbb161b68}, doi = {10.1039/c6cc10288c}, year = {2017}, date = {2017-01-01}, journal = {Chemical Communications}, volume = {53}, number = {13}, pages = {2118--2121}, abstract = {The Ugi reaction has drawn considerable attention over the years leading to numerous libraries of heterocycles and various extensions changing the nature of the components of the coupling. We report here the use of nitric acid as carboxylic acids surrogates, displaying the first aminative Ugi-type reaction leading to nitramines. © The Royal Society of Chemistry.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Ugi reaction has drawn considerable attention over the years leading to numerous libraries of heterocycles and various extensions changing the nature of the components of the coupling. We report here the use of nitric acid as carboxylic acids surrogates, displaying the first aminative Ugi-type reaction leading to nitramines. © The Royal Society of Chemistry. |
Stereoselective access to trisubstituted fluorinated alkenyl thioethers Article de journal I Fabre; T Poisson; X Pannecoucke; I Gillaizeau; I Ciofini; L Grimaud Catalysis Science and Technology, 7 (9), p. 1921–1927, 2017. @article{Fabre:2017, title = {Stereoselective access to trisubstituted fluorinated alkenyl thioethers}, author = {I Fabre and T Poisson and X Pannecoucke and I Gillaizeau and I Ciofini and L Grimaud}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85022209374&doi=10.1039%2fc7cy00076f&partnerID=40&md5=cf5efa97674f64ae4f3a3c3f98096ec0}, doi = {10.1039/c7cy00076f}, year = {2017}, date = {2017-01-01}, journal = {Catalysis Science and Technology}, volume = {7}, number = {9}, pages = {1921--1927}, abstract = {We report the first copper-catalyzed olefinic ethoxy carbonyl difluoromethylation of alkenyl thioethers via direct C-H bond functionalization using BrCF2COOEt. The developed methodology allows the preparation of trisubstituted olefins with a controlled stereochemistry. A mechanistic study is reported and a radical mechanism is revealed. © 2017 The Royal Society of Chemistry.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report the first copper-catalyzed olefinic ethoxy carbonyl difluoromethylation of alkenyl thioethers via direct C-H bond functionalization using BrCF2COOEt. The developed methodology allows the preparation of trisubstituted olefins with a controlled stereochemistry. A mechanistic study is reported and a radical mechanism is revealed. © 2017 The Royal Society of Chemistry. |
Role of Fluoride Ions in Palladium-Catalyzed Cross-Coupling Reactions Article de journal L Grimaud; A Jutand Synthesis (Germany), 49 (6), p. 1182–1189, 2017. @article{Grimaud:2017, title = {Role of Fluoride Ions in Palladium-Catalyzed Cross-Coupling Reactions}, author = {L Grimaud and A Jutand}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84995394412&doi=10.1055%2fs-0036-1588648&partnerID=40&md5=6381ca828d4aed1d86041894aa7b98e0}, doi = {10.1055/s-0036-1588648}, year = {2017}, date = {2017-01-01}, journal = {Synthesis (Germany)}, volume = {49}, number = {6}, pages = {1182--1189}, abstract = {Fluoride ions are known to promote Suzuki-Miyaura, Hiyama, and Stille reactions [cross-coupling between aryl halides ArX and nucleophiles Ar′B(OH)2, Ar′Si(OMe)3, and Ar′SnBu3, respectively], where they exert a similar triple role: (1) They favor transmetalation by formation of trans-ArPdFL2 (L = PPh3) complexes that react with the nucleophiles in contrast to trans-ArPdXL2. (2) They catalyze the reductive elimination from trans-ArPdAr′L2 generated in the transmetalation. (3) The final role is negative, by formation of unreactive anionic species [Ar′BF(OH)2]-, [Ar′SiF(OMe)3]-, or [Ar′SnFBu3]-, respectively. Consequently the rate of the rate-determining transmetalation is controlled by the concentration ratio [F-]/[nucleophile] which must be less or close to one to ensure fast transmetalation. 1 Introduction 2 Reaction of Fluoride Ions with ArPdXL2 Complexes 3 The Triple Role of Fluoride Ions in Suzuki-Miyaura Reactions 4 The Triple Role of Fluoride Ions in Hiyama Reactions 5 The Triple Role of Fluoride Ions in Stille Reactions 6 Conclusion. © 2017 Georg Thieme Verlag Stuttgart. New York.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fluoride ions are known to promote Suzuki-Miyaura, Hiyama, and Stille reactions [cross-coupling between aryl halides ArX and nucleophiles Ar′B(OH)2, Ar′Si(OMe)3, and Ar′SnBu3, respectively], where they exert a similar triple role: (1) They favor transmetalation by formation of trans-ArPdFL2 (L = PPh3) complexes that react with the nucleophiles in contrast to trans-ArPdXL2. (2) They catalyze the reductive elimination from trans-ArPdAr′L2 generated in the transmetalation. (3) The final role is negative, by formation of unreactive anionic species [Ar′BF(OH)2]-, [Ar′SiF(OMe)3]-, or [Ar′SnFBu3]-, respectively. Consequently the rate of the rate-determining transmetalation is controlled by the concentration ratio [F-]/[nucleophile] which must be less or close to one to ensure fast transmetalation. 1 Introduction 2 Reaction of Fluoride Ions with ArPdXL2 Complexes 3 The Triple Role of Fluoride Ions in Suzuki-Miyaura Reactions 4 The Triple Role of Fluoride Ions in Hiyama Reactions 5 The Triple Role of Fluoride Ions in Stille Reactions 6 Conclusion. © 2017 Georg Thieme Verlag Stuttgart. New York. |
Ugi-Smiles Couplings of Purine Derivatives Article de journal A B Abdessalem; R Abderrahim; A Dos Santos; L El Kaïm; L Grimaud Synlett, 28 (6), p. 691–694, 2017. @article{Abdessalem:2017, title = {Ugi-Smiles Couplings of Purine Derivatives}, author = {A B Abdessalem and R Abderrahim and A Dos Santos and L El Ka\"{i}m and L Grimaud}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85001574774&doi=10.1055%2fs-0036-1588117&partnerID=40&md5=9a1f6e5cb8ef3787a1e69a78dc45fd26}, doi = {10.1055/s-0036-1588117}, year = {2017}, date = {2017-01-01}, journal = {Synlett}, volume = {28}, number = {6}, pages = {691--694}, abstract = {Purines may be involved in Ugi-Smiles coupling as shown by the successful formation of thiocarboxamide derivatives from 6-mercaptopurine. This multicomponent coupling affords a very straightforward access to functionalized adenine derivatives, which are widely represented among natural products of medicinal interest. © Georg Thieme VerlagStuttgart · New York.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Purines may be involved in Ugi-Smiles coupling as shown by the successful formation of thiocarboxamide derivatives from 6-mercaptopurine. This multicomponent coupling affords a very straightforward access to functionalized adenine derivatives, which are widely represented among natural products of medicinal interest. © Georg Thieme VerlagStuttgart · New York. |
2016 |
Thrombospondin-1 Mimetic Agonist Peptides Induce Selective Death in Tumor Cells: Design, Synthesis, and Structure-Activity Relationship Studies Article de journal T Denèfle; H Boullet; L Herbi; C Newton; A -C Martinez-Torres; A Guez; E Pramil; C Quiney; M Pourcelot; M D Levasseur; E Lardé; R Moumné; F -X Ogi; P Grondin; H Merle-Beral; O Lequin; S A Susin; P Karoyan Journal of Medicinal Chemistry, 59 (18), p. 8412–8421, 2016. @article{Denefle:2016, title = {Thrombospondin-1 Mimetic Agonist Peptides Induce Selective Death in Tumor Cells: Design, Synthesis, and Structure-Activity Relationship Studies}, author = {T Den\`{e}fle and H Boullet and L Herbi and C Newton and A -C Martinez-Torres and A Guez and E Pramil and C Quiney and M Pourcelot and M D Levasseur and E Lard\'{e} and R Moumn\'{e} and F -X Ogi and P Grondin and H Merle-Beral and O Lequin and S A Susin and P Karoyan}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84988735397&doi=10.1021%2facs.jmedchem.6b00781&partnerID=40&md5=56822fdf1d99463527e7e00830952716}, doi = {10.1021/acs.jmedchem.6b00781}, year = {2016}, date = {2016-01-01}, journal = {Journal of Medicinal Chemistry}, volume = {59}, number = {18}, pages = {8412--8421}, abstract = {Thrombospondin-1 (TSP-1) is a glycoprotein considered as a key actor within the tumor microenvironment. Its binding to CD47, a cell surface receptor, triggers programmed cell death. Previous studies allowed the identification of 4N1K decapeptide derived from the TSP-1/CD47 binding epitope. Here, we demonstrate that this peptide is able to induce selective apoptosis of various cancer cell lines while sparing normal cells. A structure-activity relationship study led to the design of the first serum stable TSP-1 mimetic agonist peptide able to trigger selective programmed cell death (PCD) of at least lung, breast, and colorectal cancer cells. Altogether, these results will be of valuable interest for further investigation in the design of potent CD47 agonist peptides, opening new perspectives for the development of original anticancer therapies. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Thrombospondin-1 (TSP-1) is a glycoprotein considered as a key actor within the tumor microenvironment. Its binding to CD47, a cell surface receptor, triggers programmed cell death. Previous studies allowed the identification of 4N1K decapeptide derived from the TSP-1/CD47 binding epitope. Here, we demonstrate that this peptide is able to induce selective apoptosis of various cancer cell lines while sparing normal cells. A structure-activity relationship study led to the design of the first serum stable TSP-1 mimetic agonist peptide able to trigger selective programmed cell death (PCD) of at least lung, breast, and colorectal cancer cells. Altogether, these results will be of valuable interest for further investigation in the design of potent CD47 agonist peptides, opening new perspectives for the development of original anticancer therapies. © 2016 American Chemical Society. |
Multi-Stage Mass Spectrometry Analysis of Sugar-Conjugated β-Turn Structures to be Used as Probes in Autoimmune Diseases Article de journal C Giangrande; N Auberger; C Rentier; A M Papini; J -M Mallet; S Lavielle; J Vinh Journal of the American Society for Mass Spectrometry, 27 (4), p. 735–747, 2016. @article{Giangrande:2016, title = {Multi-Stage Mass Spectrometry Analysis of Sugar-Conjugated β-Turn Structures to be Used as Probes in Autoimmune Diseases}, author = {C Giangrande and N Auberger and C Rentier and A M Papini and J -M Mallet and S Lavielle and J Vinh}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84962245067&doi=10.1007%2fs13361-015-1321-9&partnerID=40&md5=404714782b302b757b996434cc44a993}, doi = {10.1007/s13361-015-1321-9}, year = {2016}, date = {2016-01-01}, journal = {Journal of the American Society for Mass Spectrometry}, volume = {27}, number = {4}, pages = {735--747}, abstract = {Synthetic sugar-modified peptides were identified as antigenic probes in the context of autoimmune diseases. The aim of this work is to provide a mechanistic study on the fragmentation of different glycosylated analogs of a synthetic antigenic probe able to detect antibodies in a subpopulation of multiple sclerosis patients. In particular the N-glucosylated type I′ β-turn peptide structure called CSF114(Glc) was used as a model to find signature fragmentations exploring the potential of multi-stage mass spectrometry by MALDI-LTQ Orbitrap. Here we compare the fragmentation of the glucosylated form of the synthetic peptide CSF114(Glc), bearing a glucose moiety on an asparagine residue, with less or non- immunoreactive forms, bearing different sugar-modifications, such as CSF114(GlcNAc), modified with a residue of N-acetylglucosamine, and CSF114[Lys7(1-deoxyfructopyranosyl)], this last one modified with a 1-deoxyfructopyranosyl moiety on a lysine at position 7. The analysis was set up using a synthetic compound specifically deuterated on the C-1 to compare its fragmentation with the fragmentation of the undeuterated form, and thus ascertain with confidence the presence on an Asn(Glc) within a peptide sequence. At the end of the study, our analysis led to the identification of signature neutral losses inside the sugar moieties to characterize the different types of glycosylation/glycation. The interest of this study lies in the possibility of applyimg this approach to the discovery of biomarkers and in the diagnosis of autoimmune diseases. © American Society for Mass Spectrometry 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Synthetic sugar-modified peptides were identified as antigenic probes in the context of autoimmune diseases. The aim of this work is to provide a mechanistic study on the fragmentation of different glycosylated analogs of a synthetic antigenic probe able to detect antibodies in a subpopulation of multiple sclerosis patients. In particular the N-glucosylated type I′ β-turn peptide structure called CSF114(Glc) was used as a model to find signature fragmentations exploring the potential of multi-stage mass spectrometry by MALDI-LTQ Orbitrap. Here we compare the fragmentation of the glucosylated form of the synthetic peptide CSF114(Glc), bearing a glucose moiety on an asparagine residue, with less or non- immunoreactive forms, bearing different sugar-modifications, such as CSF114(GlcNAc), modified with a residue of N-acetylglucosamine, and CSF114[Lys7(1-deoxyfructopyranosyl)], this last one modified with a 1-deoxyfructopyranosyl moiety on a lysine at position 7. The analysis was set up using a synthetic compound specifically deuterated on the C-1 to compare its fragmentation with the fragmentation of the undeuterated form, and thus ascertain with confidence the presence on an Asn(Glc) within a peptide sequence. At the end of the study, our analysis led to the identification of signature neutral losses inside the sugar moieties to characterize the different types of glycosylation/glycation. The interest of this study lies in the possibility of applyimg this approach to the discovery of biomarkers and in the diagnosis of autoimmune diseases. © American Society for Mass Spectrometry 2016. |
Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease Article de journal E Quévrain; M A Maubert; C Michon; F Chain; R Marquant; J Tailhades; S Miquel; L Carlier; L G Bermúdez-Humarán; B Pigneur; O Lequin; P Kharrat; G Thomas; D Rainteau; C Aubry; N Breyner; C Afonso; S Lavielle; J -P Grill; G Chassaing; J M Chatel; G Trugnan; R Xavier; P Langella; H Sokol; P Seksik Gut, 65 (3), p. 415–425, 2016. @article{Quevrain:2016, title = {Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease}, author = {E Qu\'{e}vrain and M A Maubert and C Michon and F Chain and R Marquant and J Tailhades and S Miquel and L Carlier and L G Berm\'{u}dez-Humar\'{a}n and B Pigneur and O Lequin and P Kharrat and G Thomas and D Rainteau and C Aubry and N Breyner and C Afonso and S Lavielle and J -P Grill and G Chassaing and J M Chatel and G Trugnan and R Xavier and P Langella and H Sokol and P Seksik}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84960373289&doi=10.1136%2fgutjnl-2014-307649&partnerID=40&md5=74f8eb656f288a29a96faffebf9c2ee5}, doi = {10.1136/gutjnl-2014-307649}, year = {2016}, date = {2016-01-01}, journal = {Gut}, volume = {65}, number = {3}, pages = {415--425}, abstract = {Background: Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. Methods: Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Antiinflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. Results: The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-?B pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice. Conclusions: A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. Methods: Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Antiinflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. Results: The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-?B pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice. Conclusions: A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model. |
How to unveil self-quenched fluorophores and subsequently map the subcellular distribution of exogenous peptides Article de journal J -M Swiecicki; F Thiebaut; M Di Pisa; S Gourdin -Bertin; J Tailhades; C Mansuy; F Burlina; S Chwetzoff; G Trugnan; G Chassaing; S Lavielle Scientific Reports, 6 , 2016. @article{Swiecicki:2016, title = {How to unveil self-quenched fluorophores and subsequently map the subcellular distribution of exogenous peptides}, author = {J -M Swiecicki and F Thiebaut and M Di Pisa and S Gourdin -Bertin and J Tailhades and C Mansuy and F Burlina and S Chwetzoff and G Trugnan and G Chassaing and S Lavielle}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84957837107&doi=10.1038%2fsrep20237&partnerID=40&md5=3b6ebb5cc1852323b58fc293948a9914}, doi = {10.1038/srep20237}, year = {2016}, date = {2016-01-01}, journal = {Scientific Reports}, volume = {6}, abstract = {Confocal laser scanning microscopy (CLSM) is the most popular technique for mapping the subcellular distribution of a fluorescent molecule and is widely used to investigate the penetration properties of exogenous macromolecules, such as cell-penetrating peptides (CPPs), within cells. Despite the membrane-association propensity of all these CPPs, the signal of the fluorescently labeled CPPs did not colocalize with the plasma membrane. We studied the origin of this fluorescence extinction and the overall consequence on the interpretation of intracellular localizations from CLSM pictures. We demonstrated that this discrepancy originated from fluorescence self-quenching. The fluorescence was unveiled by a "dilution" protocol, i.e. by varying the ratio fluorescent/non-fluorescent CPP. This strategy allowed us to rank with confidence the subcellular distribution of several CPPs, contributing to the elucidation of the penetration mechanism. More generally, this study proposes a broadly applicable and reliable method to study the subcellular distribution of any fluorescently labeled molecules.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Confocal laser scanning microscopy (CLSM) is the most popular technique for mapping the subcellular distribution of a fluorescent molecule and is widely used to investigate the penetration properties of exogenous macromolecules, such as cell-penetrating peptides (CPPs), within cells. Despite the membrane-association propensity of all these CPPs, the signal of the fluorescently labeled CPPs did not colocalize with the plasma membrane. We studied the origin of this fluorescence extinction and the overall consequence on the interpretation of intracellular localizations from CLSM pictures. We demonstrated that this discrepancy originated from fluorescence self-quenching. The fluorescence was unveiled by a "dilution" protocol, i.e. by varying the ratio fluorescent/non-fluorescent CPP. This strategy allowed us to rank with confidence the subcellular distribution of several CPPs, contributing to the elucidation of the penetration mechanism. More generally, this study proposes a broadly applicable and reliable method to study the subcellular distribution of any fluorescently labeled molecules. |
Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes Article de journal A Kamah; F X Cantrelle; I Huvent; J Giustiniani; K Guillemeau; C Byrne; Y Jacquot; I Landrieu; E E Baulieu; C Smet; B Chambraud; G Lippens Journal of Molecular Biology, 428 (6), p. 1080–1090, 2016. @article{Kamah:2016, title = {Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes}, author = {A Kamah and F X Cantrelle and I Huvent and J Giustiniani and K Guillemeau and C Byrne and Y Jacquot and I Landrieu and E E Baulieu and C Smet and B Chambraud and G Lippens}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84959261786&doi=10.1016%2fj.jmb.2016.02.015&partnerID=40&md5=fa8b175818d6093a38424aca150b0eb2}, doi = {10.1016/j.jmb.2016.02.015}, year = {2016}, date = {2016-01-01}, journal = {Journal of Molecular Biology}, volume = {428}, number = {6}, pages = {1080--1090}, abstract = {The aggregation of the neuronal Tau protein is one molecular hallmark of Alzheimer's disease and other related tauopathies, but the precise molecular mechanisms of the aggregation process remain unclear. The FK506 binding protein FKBP52 is able to induce oligomers in the pathogenic Tau P301L mutant and in a truncated form of the wild-type human Tau protein. Here, we investigate whether FKBP52's capacity to induce Tau oligomers depends on its prolyl cis/trans isomerase activity. We find that FKBP52 indeed can isomerize selected prolyl bonds in the different Tau proteins, and that this activity is carried solely by its first FK506 binding domain. Its capacity to oligomerize Tau is, however, not linked to this peptidyl-prolyl isomerase activity. In addition, we identified a novel molecular interaction implying the PHF6 peptide of Tau and the FK1/FK2 domains of FKBP52 independent of FK506 binding; these data point toward a non-catalytic molecular interaction that might govern the effect of FKBP52 on Tau. © 2016 Elsevier Ltd. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The aggregation of the neuronal Tau protein is one molecular hallmark of Alzheimer's disease and other related tauopathies, but the precise molecular mechanisms of the aggregation process remain unclear. The FK506 binding protein FKBP52 is able to induce oligomers in the pathogenic Tau P301L mutant and in a truncated form of the wild-type human Tau protein. Here, we investigate whether FKBP52's capacity to induce Tau oligomers depends on its prolyl cis/trans isomerase activity. We find that FKBP52 indeed can isomerize selected prolyl bonds in the different Tau proteins, and that this activity is carried solely by its first FK506 binding domain. Its capacity to oligomerize Tau is, however, not linked to this peptidyl-prolyl isomerase activity. In addition, we identified a novel molecular interaction implying the PHF6 peptide of Tau and the FK1/FK2 domains of FKBP52 independent of FK506 binding; these data point toward a non-catalytic molecular interaction that might govern the effect of FKBP52 on Tau. © 2016 Elsevier Ltd. All rights reserved. |
A β-turn motif in the steroid hormone receptor's ligand-binding domains interacts with the peptidyl-prolyl isomerase (PPIase) catalytic site of the immunophilin FKBP52 Article de journal C Byrne; M A Henen; M Belnou; F -X Cantrelle; A Kamah; H Qi; J Giustiniani; B Chambraud; E -E Baulieu; G Lippens; I Landrieu; Y Jacquot Biochemistry, 55 (38), p. 5366–5376, 2016. @article{Byrne:2016, title = {A β-turn motif in the steroid hormone receptor's ligand-binding domains interacts with the peptidyl-prolyl isomerase (PPIase) catalytic site of the immunophilin FKBP52}, author = {C Byrne and M A Henen and M Belnou and F -X Cantrelle and A Kamah and H Qi and J Giustiniani and B Chambraud and E -E Baulieu and G Lippens and I Landrieu and Y Jacquot}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84989260723&doi=10.1021%2facs.biochem.6b00506&partnerID=40&md5=d6d3646263e00c9bd3049c235c894a13}, doi = {10.1021/acs.biochem.6b00506}, year = {2016}, date = {2016-01-01}, journal = {Biochemistry}, volume = {55}, number = {38}, pages = {5366--5376}, abstract = {The immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor α (hERα) and using nuclear magnetic resonance, we show here that the short V364PGF367 sequence, which is located within its ligand-binding domain and adopts a type II β-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics. An increase in the hydrophobicity of the residue preceding the proline and cyclization of the VPGF peptide strengthen its recognition by the FK1 domain of FKBP52. Replacement of the Pro residue with a dimethylproline also enhances this interaction. Our study not only contributes to a better understanding of how the interaction between the FK1 domain of FKBP52 and steroid hormone receptors most likely works but also opens new avenues for the synthesis of FKBP52 FK1 peptide ligands appropriate for the control of hormone-dependent physiological mechanisms or of the functioning of the Tau protein. Indeed, it has been shown that FKBP52 is involved in the intraneuronal dynamics of the Tau protein. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor α (hERα) and using nuclear magnetic resonance, we show here that the short V364PGF367 sequence, which is located within its ligand-binding domain and adopts a type II β-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics. An increase in the hydrophobicity of the residue preceding the proline and cyclization of the VPGF peptide strengthen its recognition by the FK1 domain of FKBP52. Replacement of the Pro residue with a dimethylproline also enhances this interaction. Our study not only contributes to a better understanding of how the interaction between the FK1 domain of FKBP52 and steroid hormone receptors most likely works but also opens new avenues for the synthesis of FKBP52 FK1 peptide ligands appropriate for the control of hormone-dependent physiological mechanisms or of the functioning of the Tau protein. Indeed, it has been shown that FKBP52 is involved in the intraneuronal dynamics of the Tau protein. © 2016 American Chemical Society. |