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See detailFrom Metabolomics Study of Age-Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase Inhibitors (PDK)
Arslan, Deniz ULiege; Schoumacher, Matthieu ULiege; Pirotte, Bernard ULiege et al

Poster (2017, September 14)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of the retina specialized for the high-acuity vision. Exudative AMD, called “wet”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, have demonstrated that lactate level is clearly involved in the severity of the pathology as well as the relationship between lactate, CNV and AMD [1]. According to this result, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. PDK and its four isoforms (PDK1-4) regulate the activity of the pyruvate dehydrogenase complex (PDH), a mitochondrial enzyme that plays a major role in the metabolic pathway of glucose, by reversible phosphorylation. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment opportunities in AMD disease. Different analogues of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (fig.1) have been already synthetized and pharmacological evaluation is currently in progress. According to the results obtained, various pharmacomodulations will be investigated. [less ▲]

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See detailDesign and Synthesis of [18F]BPAM121, a PET-Probe Targeting AMPA-subtype Glutamatergic Receptors.
Manos-Turvey, Alexandra ULiege; Lemaire, Christian ULiege; Becker, Guillaume ULiege et al

Poster (2017, August)

AMPA receptors (AMPARs), one of three sub-groups of ionotropic glutamate receptors present in the central nervous system, are recognised for their involvement in long-term potentiation (LTP), and learning ... [more ▼]

AMPA receptors (AMPARs), one of three sub-groups of ionotropic glutamate receptors present in the central nervous system, are recognised for their involvement in long-term potentiation (LTP), and learning and memory processes. [1] They represent a valid cognitive enhancer target, particularly in the fight against Alzheimer’s disease (AD). [2,3] Benzothiadiazine 1,1-dioxides, such as BPAM121, have emerged as important allosteric modulators of AMPARs, working solely in the presence of the endogenous transmitter. [4] Synthesis of BPAM121 labelled with fluorine-18 was proposed, to investigate the utility of this molecule as a PET probe in vivo, and evaluate its potential as an AD diagnostic tool (Figure 1). [Figure 1. a) Structure of BPAM121, b) Established radiochemical synthesis of [18F]BPAM121.] This work documents the successful optimization of synthesis, purification and formulation of [18F]BPAM121 using an automated FASTlab (GE Healthcare) synthesizer. In particular, the influence of higher-level [18F]fluoride ion starting concentrations on final product formulation requirements is discussed. Initial results revealed [18F]BPAM121 successfully passes the blood brain barrier, and further biological studies are currently underway. References [1] S. F. Traynelis et al. Pharmacol. Rev. 2010, 62, 405-496. 
 [2] J. Keifer, Z. Zheng, Eur. J. Neurosci. 2010, 32, 269-277. 
 [3] L. Gao et al. J. Neurochem. 2016, 136, 620-636. 
 [4] P. Francotte et al. J. Med. Chem. 2010, 53, 1700-1711. 
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See detailDiscovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines
Schnekenburger, M; Goffin, Eric ULiege; Lee, J-Y et al

in Journal of Medicinal Chemistry (2017), 60(11), 4714-4733

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting ... [more ▼]

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors. [less ▲]

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See detailActivation of the orphan G protein-coupled receptor GPR27 by surrogate ligands promotes β-arrestin 2 recruitment
Dupuis, Nadine ULiege; Laschet, Céline ULiege; Franssen, Delphine ULiege et al

in Molecular Pharmacology (2017), 91(6), 595-608

G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by ... [more ▼]

G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by a high level of conservation among vertebrates and a predominant expression in the central nervous system. In addition, it has recently been linked to insulin secretion. However, the absence of endogenous or surrogate ligands for GPR27 complicates the examination of its biological function. Our aim was to validate GPR27 signaling pathways and therefore we sought to screen a diversity oriented synthesis library to identify GPR27-specific surrogate agonists. In order to select an optimal screening assay, we investigated GPR27 ligand-independent activity. Both in G protein-mediated pathways and in β-arrestin 2 recruitment, no ligand-independent activity could be measured. However, we observed a recruitment of β-arrestin 2 to a GPR27V2 chimera in the presence of membrane-anchored β-adrenergic receptor kinase 1 (GRK2). Therefore, we optimized a firefly luciferase complementation assay to screen against this chimeric receptor. We identified two compounds (N-[4-(anilinocarbonyl)phenyl]-2,4-dichlorobenzamide (ChemBridge ID5128535) and 2,4-dichloro-N-{4-[(1,3-thiazol-2-ylamino)sulfonyl]phenyl}benzamide (ChemBridge ID5217941)) sharing a N-phenyl-2,4-dichlorobenzamide scaffold, which were selective for GPR27 over its closely related family members GPR85 and GPR173. The specificity of the activity was confirmed with a NanoBiT® β-arrestin 2 assay, imaging of GFP-tagged β-arrestin 2 and PathHunter® β-arrestin 2 Assay. Interestingly, no G protein activation was detected upon activation of GPR27 by these compounds. Our study provides the first selective surrogate agonists for the orphan GPR27. [less ▲]

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See detail[18F]BPAM121: An AMPAR Modulator with Potential as a PET Probe
Manos-Turvey, Alexandra ULiege; Lemaire, Christian ULiege; Deverdenne, François et al

Poster (2017, June)

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See detailIdentification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors
Larsen, Anja Probst; Fièvre, Sabine; Frydenvang, Karla et al

in Molecular Pharmacology (2017), 91

Kainate receptors (KARs) consist of a class of ionotropic gluta- mate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits ... [more ▼]

Kainate receptors (KARs) consist of a class of ionotropic gluta- mate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of (S)-2- amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptors have been reported, no such ligands are avail- able for KARs. In this study, we investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1- dioxide (BPAM344) potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 mM), with an EC50 of 79 mM. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. 4-cyclopropyl-7-hydroxy-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM521) potentiated the recorded peak current amplitude of GluK2a 12-fold at a concen- tration of 300 mM with an EC50 value of 159 mM, whereas no potentiation of the glutamate-evoked response was observed for 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM121) at the highest concentration of modulator tested (300 mM). BPAM344 (100 mM) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15- fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1i (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator- binding sites at the GluK1 dimer interface. In conclusion, this study may enable the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigation of the function of KARs in vivo and may prove useful for pharmacologically controlling the activity of neuronal networks. [less ▲]

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See detailGPR101 orphan GPCR: a novel cause of growth hormone deregulation
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

Poster (2017, May)

GPR101 is an orphan G-protein coupled receptor with unknown ligand. In 2014, an international study clearly pointed to a strong association between this receptor and the X-linked acrogigantism (X-LAG ... [more ▼]

GPR101 is an orphan G-protein coupled receptor with unknown ligand. In 2014, an international study clearly pointed to a strong association between this receptor and the X-linked acrogigantism (X-LAG) syndrome, which begins in childhood and causes the “tallest giants”. The children (carriers of the GPR101 duplication on the X chromosome) grow abnormally even before they are one year old, secrete phenomenal quantities of growth hormone, and develop pituitary adenomas that do not respond to current therapies. The mechanism by which GPR101 contributes to increased growth hormone secretion is currently not known. Nevertheless, the lack of mechanistic insight into the function of GPR101 precludes its validation as a drug target. This lack of knowledge on GPR101 is the consequence of the paucity of specific pharmacological/research tools currently available. Therefore, we propose to study GPR101 functions and its role in growth hormone regulation. First, we determined the receptor cellular localization. We also deciphered its constitutive signalling pathways by detecting high cAMP levels. We completed our study with an examination of receptor coupling to other pathways and G proteins. Furthermore, we applied targeted mutagenesis to modulate the receptor constitutive activity in order to understand the receptor function at a molecular level. These GPR101 mutants will help us to understand the role of this receptor in GH regulation and/or to treat people suffering from pituitary dysfunction. This information is an absolute prerequisite to link molecular pharmacology of GPR101 with physiological functions. [less ▲]

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See detailDiscovery and pharmacological characterization of succinate receptor (SUCNR1/GPR91) agonists
Geubelle, Pierre ULiege; Gilissen, Julie; Dilly, Sebastien et al

in British Journal of Pharmacology (2017), 174(9), 796-808

Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho ... [more ▼]

Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists. Experimental Approach We screened a library of succinate analogues and analysed their activity on SUCNR1. In addition, we modelled a pharmacophore and a binding site for the receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilisation, TGF-α shedding and recruitment of arrestin 3. The in vivo impact of SUCNR1 activation by these new agonists was evaluated on rat blood pressure. Key Results We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to the one of succinic acid. Interestingly, cis-epoxysuccinic acid was characterized by a 10 to 20 fold higher potency than succinate on the receptor. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM) as compared to succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all bioassays tested. In vivo, cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid increased rat blood pressure to the same extent as succinate did. Conclusions and Implications We provide new agonist tools for SUCNR1 that should facilitate further research on this understudied receptor. [less ▲]

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See detailSmall molecule ligands for the orphan GPR27
Dupuis, Nadine ULiege; Franssen, Delphine ULiege; Laschet, Céline ULiege et al

Poster (2016, September 26)

Background G protein-coupled receptors (GPCRs) are involved in many physiological processes and constitute the target of around 30% of marketed therapies. Nonetheless, ~100 human GPCRs have no known ... [more ▼]

Background G protein-coupled receptors (GPCRs) are involved in many physiological processes and constitute the target of around 30% of marketed therapies. Nonetheless, ~100 human GPCRs have no known ligand and are designated as "orphan". This project focuses on GPR27, a rhodopsin-like alpha orphan of the SREB family (Super conserved Receptors Expressed in the Brain), presumably involved in the regulation of insulin secretion [1]. Methods In order to identify small molecules activating GPR27, we developed a firefly luciferase complementation assay (based on [2]) to assess the binding of ß-arrestin2 to the activated GPCR. To increase the affinity for and strengthen the interaction with ß-arrestin2, a GPR27-V2R chimera has been used for library screening. Results Small molecules activating GPR27-V2 have been identified in the DiverSetTM library (ChemBridge). After exclusion of non-specific activities using another unrelated GPCR, two compounds sharing a common scaffold with activity in the low micromolar range were selected for further investigations. We confirmed their agonist profile by performing complete concentration-response curves on our arrestin complementation assay as well as orthogonal assays. These compounds show good specificity being inactive on GPR85-V2 and GPR173-V2 (the two other SREB members). With these original tools, we characterized the recruitment of ß-arrestin2 to activated GPR27 WT. Conclusion We identified small molecule ligands for GPR27 that will serve as valuable tools for studying the pharmacology of GPR27 as well as its physiological roles, for example in insulin secretion. 1 Ku G.M., Pappalardo Z., Luo C.C., German M.S., McManus M.T. An siRNA Screen in Pancreatic Beta Cells Reveals a Role for Gpr27 in Insulin Production. PLoS genetics. 2012, 8, e1002449. 2 Takakura H., Hattori M., Takeuchi M., Ozawa T. Visualization and Quantitative Analysis of G Protein-Coupled Receptor−β-Arrestin Interaction in Single Cells and Specific Organs of Living Mice Using Split Luciferase Complementation. ACS Chem. Biol. 2012, 7, 901−910. [less ▲]

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See detailEnthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2
Krintel, Christian; Francotte, Pierre ULiege; Pickering, Darryl S. et al

in Biophysical Journal (2016), 110

The 1,2,4-benzothiadiazine 1,1-dioxide type of positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for the treatment of cognitive disorders, e.g ... [more ▼]

The 1,2,4-benzothiadiazine 1,1-dioxide type of positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for the treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind in a cleft formed by the interface of two neighboring ligand binding domains and act by stabilizing the agonist-bound open- channel conformation. The driving forces behind the binding of these modulators can be significantly altered with only minor substitutions to the parent molecules. In this study, we show that changing the 7-fluorine substituent of modulators BPAM97 (2) and BPAM344 (3) into a hydroxyl group (BPAM557 (4) and BPAM521 (5), respectively), leads to a more favorable binding enthalpy (DH, kcal/mol) from 4.9 (2) and 7.5 (3) to 6.2 (4) and 14.5 (5), but also a less favorable binding entropy ( TDS, kcal/mol) from 2.3 (2) and 1.3 (3) to 0.5 (4) and 4.8 (5). Thus, the dissociation constants (Kd, mM) of 4 (11.2) and 5 (0.16) are similar to those of 2 (5.6) and 3 (0.35). Functionally, 4 and 5 potentiated responses of 10 mM L-glutamate at homomeric rat GluA2(Q)i receptors with EC50 values of 67.3 and 2.45 mM, respectively. The binding mode of 5 was examined with x-ray crystallography, showing that the only change compared to that of earlier compounds was the orientation of Ser-497 pointing toward the hydroxyl group of 5. The favorable enthalpy can be explained by the formation of a hydrogen bond from the side-chain hydroxyl group of Ser-497 to the hydroxyl group of 5, whereas the unfavorable entropy might be due to desolva- tion effects combined with a conformational restriction of Ser-497 and 5. In summary, this study shows a remarkable example of enthalpy-entropy compensation in drug development accompanied with a likely explanation of the underlying structural mechanism. [less ▲]

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See detailDESIGN OF HIGH-AFFINITY LIGANDS FOR THE BENZOTHIADIAZINE ALLOSTERIC BINDING SITE OF THE AMPA RECEPTORS
Drapier, Thomas ULiege; Geubelle, Pierre ULiege; Bouckaert, Charlotte et al

Poster (2016, May 26)

L-glutamic acid is the major excitatory neurotransmitter in the brain. It exerts its effects through metabotropic and ionotropic receptors. Among the latter, three subtypes have been identified: NMDA ... [more ▼]

L-glutamic acid is the major excitatory neurotransmitter in the brain. It exerts its effects through metabotropic and ionotropic receptors. Among the latter, three subtypes have been identified: NMDA, AMPA and KA receptors. It is now well established that a deficit in glutamatergic signaling may be responsible for neurological disorders such as mild cognitive impairment, schizophrenia, depression, and ADHD. Enhancement of the signal through positive allosteric modulators of AMPA receptors might be a therapeutic issue for these diseases. These compounds are expected to exert a fine tuning of the signal. Since they require the presence of the endogenous ligand to be active, they are expected to induce less toxicity than agonists. In this context, based on the structure of known allosteric modulators of AMPA receptors such as cyclothiazide and IDRA 21, the Laboratory of Medicinal Chemistry (University of Liège) has developed a series of 1,2,4-benzothiadiazine 1,1-dioxides with high potency as AMPA receptor potentiators. Crystallographic data obtained by the Department of Drug Design and Pharmacology (University of Copenhagen) highlighted those potentiators bind to two contiguous sites at the dimer interface of the ligand binding domain (LBD) of the AMPA receptor1,2. Based on these data, we may expect that the synthesis of dimeric molecules could lead to further improvement in affinity and activity. This assumption was reinforced by docking experiments conducted with virtual examples of dimeric compounds on the GluA2-LBD (collaboration with NAMEDIC). The present work is thus focusing on the preparation of a family of dimeric benzothiadiazine dioxides. Moreover, in collaboration with GIGA-Molecular Pharmacology, we are developing a pharmacological in vitro assay based on the measurement of Ca2+ inflow through a fluorimetric method. This medium-throughput screening will enable the characterization of our new compounds and the validation of our working hypothesis. [less ▲]

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See detailFrom Metabolomics Study of Age-Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase Inhibitors (PDK)
Arslan, Deniz ULiege; Schoumacher, Matthieu ULiege; Pirotte, Bernard ULiege et al

Poster (2016, May)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of the retina specialized for the high-acuity vision. Exudative AMD, called “wet”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, have demonstrated that lactate level is clearly involved in the severity of the pathology as well as the relationship between lactate, CNV and AMD. According to this result, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. PDK and its four isoforms (PDK1-4) regulate the activity of the pyruvate dehydrogenase complex (PDH), a mitochondrial enzyme that plays a major role in the metabolic pathway of glucose, by reversible phosphorylation. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment opportunities in AMD disease. Different analogues of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (fig.1) have been already synthetized and pharmacological evaluation is currently in progress. According to the results obtained, various pharmacomodulations will be investigated [less ▲]

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See detailFrom Metabolomics to Identification of a new therapeutic approach for Age-Related Macular Degeneration (AMD)
Schoumacher, Matthieu ULiege; De Tullio, Pascal ULiege; LAMBERT, Vincent ULiege et al

Poster (2016, May)

Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD result from the exudative form, which is ... [more ▼]

Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood and critical issues remain to be addressed. Metabolomics is defined as the comprehensive study of endogenous metabolites changes in various biological systems. This newly emerging “omic” science provides a unique opportunity to correlate variation of the metabolome with pathological occurrence or progression and/or to identify metabolites that are implicated in the disease. We apply a 1H NMR metabolomics approach on sera collected from AMD patient and healthy volunteers and form a mice model of laser-induced CNV which mimics the effect of exudative AMD. After post-processing treatments, the different spectra were analyzed by statistical discriminant methodologies (PCA, ICA, PLS-DA, O-PLS-DA). These approaches allow the differentiation between control and AMD patients and between laser-induced mice and the control mice group. Moreover, the same discriminating spectral zones have been identified in human and mice model, leading to the emergence of different putative biomarkers. Among these markers, lactate emerges as a key metabolite in both settings. Mechanistically, lactate produced locally and by inflammatory cells, plays a critical role in the onset of the inflammatory and angiogenic phases. In mice model of laser-induced CNV, normalization of circulating lactate by dichloroacetate a pyruvate dehydrogenase kinase (PDK) inhibitor, decreases CNV development. Our data support the innovative concept of lactate as a parainflammation- and angio-metabolite associated to AMD and CNV progression. Moreover, control of blood lactate level via inhibition of PDK provides new options for the treatment of exudative AMD. This study demonstrates the ability of metabolomics for drug target discovery and opens new perspectives for AMD treatment and patient follow-up. [less ▲]

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See detailEffect of Ribes nigrum leaf extracts on endothelium-dependent vasorelaxation
Tabart, Jessica; Shini-Kerth, Valérie; PINCEMAIL, Joël ULiege et al

Poster (2016, April 22)

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See detailIdentification of small molecule ligands for the orphan GPCR GPR27
Dupuis, Nadine ULiege; Gilissen, Julie; Derj, Anouar ULiege et al

Poster (2016, January 25)

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See detailTargeted and random mutagenesis of orphan GPCRs of the SREB family
Laschet, Céline ULiege; Dupuis, Nadine ULiege; Derj, Anouar ULiege et al

Poster (2016, January 25)

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See detailMetabolomics as a Challenging Approach for Medicinal Chemistry and Personalized Medicine.
Frederich, Michel ULiege; Pirotte, Bernard ULiege; Fillet, Marianne ULiege et al

in Journal of Medicinal Chemistry (2016), 59(19), 86498666

"Omics" sciences have been developed to provide a holistic point of view of biology and to better understand the complexity of an organism as a whole. These systems biology approaches can be examined at ... [more ▼]

"Omics" sciences have been developed to provide a holistic point of view of biology and to better understand the complexity of an organism as a whole. These systems biology approaches can be examined at different levels, starting from the most fundamental, i.e., the genome, and finishing with the most functional, i.e., the metabolome. Similar to how genomics is applied to the exploration of DNA, metabolomics is the qualitative and quantitative study of metabolites. This emerging field is clearly linked to genomics, transcriptomics, and proteomics. In addition, metabolomics provides a unique and direct vision of the functional outcome of an organism's activities that are required for it to survive, grow, and respond to internal and external stimuli or stress, e.g., pathologies and drugs. The links between metabolic changes, patient phenotype, physiological and/or pathological status, and treatment are now well established and have opened a new area for the application of metabolomics in the drug discovery process and in personalized medicine. [less ▲]

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See detailThe leaf extract of Ribes nigrum L. is a potent stimulator of the endothelial formation of NO in cultured endothelial cells and porcine coronary artery rings
Tabart, Jessica; Schini-Kerth, Valérie; PINCEMAIL, Joël ULiege et al

in Journal of Berry Research (2016), 6

BACKGROUND: Endothelial dysfunction is a major hallmark of most types of cardiovascular diseases. Numerous plant extracts have been shown to cause endothelium-dependent relaxations by increasing the ... [more ▼]

BACKGROUND: Endothelial dysfunction is a major hallmark of most types of cardiovascular diseases. Numerous plant extracts have been shown to cause endothelium-dependent relaxations by increasing the endothelial formation of the potent vasoprotective factor, nitric oxide (NO). OBJECTIVE: The ability of different Ribes nigrum L. extracts (Grossulariaceae) to induce endothelium-dependent relaxation by stimulating the endothelial formation of NO was assesssed. METHODS: Ribes nigrum extracts were prepared from buds, berries and leaves by extraction (Acetone:H2O:Acetic Acid; 70/28/2 (v/v/v)) and lyophilized after acetone evaporation. The ability of the extracts to stimulate the endothelial formation of NO was assessed using cultured endothelial cells and isolated porcine coronary artery rings. RESULTS: The Ribes nigrum leaf extract increased to a greater extent than the bud and the berry extracts the formation of NO, and up-regulated eNOS mRNA expression in cultured endothelial cells (the stimulatory effects amounted to 197 ± 9 %, 134 ± 6 % and 118 ± 5 %, respectively). The leaf extract induced greater relaxations of isolated coronary arteries with endothelium than the bud and the berry extracts whereas no such effects were observed in rings without endothelium. Relaxations to the leaf extract were minimally affected by indomethacin and by inhibitors of endothelium-dependent hyperpolarization response, and markedly reduced by NG-nitro-L-arginine. CONCLUSIONS: The present findings indicate that the Ribes nigrum leaf extract is a more potent inducer of the endothelial formation of NO than the bud and the berry extracts. [less ▲]

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