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

in Molecular Pharmacology (in press)

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

in British Journal of Pharmacology (in press)

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 detailChemokine neutralization as an innovative therapeutic strategy for atopic dermatitis
Abboud, Dayana ULg; Hanson, Julien ULg

in Drug Discovery Today (in press)

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See detailSmall molecule ligands for the orphan GPR27
Dupuis, Nadine ULg; Franssen, Delphine ULg; Laschet, Céline ULg 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 detailTargeted mutagenesis of orphan GPCRs of the SREB family
Laschet, Céline ULg; Dupuis, Nadine ULg; Soni, Arvind ULg et al

Poster (2016, September)

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See detailHuman herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7
Szpakowska, Martyna; Dupuis, Nadine ULg; Baragli, Alessandra et al

in Biochemical Pharmacology (2016), 114

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See detailDESIGN OF HIGH-AFFINITY LIGANDS FOR THE BENZOTHIADIAZINE ALLOSTERIC BINDING SITE OF THE AMPA RECEPTORS
Drapier, Thomas ULg; Geubelle, Pierre ULg; 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 detailA forskolin free method for measuring cAMP modulation by Gi coupled receptors
Hanson, Julien ULg

Conference (2016, April 18)

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

Poster (2016, January 25)

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

Poster (2016, January 25)

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See detailGPCRs in immunity: atypical receptors and novel concepts
Hanson, Julien ULg; Chevigné, Andy

in Biochemical Pharmacology (2016)

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See detailInsight into SUCNR1 (GPR91) structure and function
Gilissen, Julie ULg; Jouret, François ULg; Pirotte, Bernard ULg et al

in Pharmacology & Therapeutics (2016)

SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs ... [more ▼]

SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate. According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy. The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor,more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed. [less ▲]

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See detailDesign, synthesis and pharmacological evaluation of dimeric ligands for the benzothiadiazine dioxide allosteric binding site of the AMPA receptors
Drapier, Thomas ULg; Francotte, Pierre ULg; Pirotte, Bernard ULg et al

Conference (2015, June 04)

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 schizophrenia, depression, mild cognitive impairment 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 (1) and IDRA 21 (2), 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, among which compounds (3) and (4). Crystallographic data obtained by the Department of Medicinal Chemistry (University of Copenhagen) highlighted that (3) and (4) bind to two contiguous sites at the dimer interface of the ligand binding domain of the AMPA receptor1,2. From these data, we may expect that the synthesis of dimeric molecules could lead to further improvement in affinity and activity. Our work consists in the development of a family of dimeric benzothiadiazine dioxides and their evaluation in a pharmacological assay. Several structural parameters such as the position of the bridge on the aromatic ring between the two heterocycles as well as its nature and length will be studied in order to determine their impact on the activity and thus the affinity. [less ▲]

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See detailßarrestin coupling of the orphan GPCR GPR27
Dupuis, Nadine ULg; Gilissen, Julie ULg; Derj, Anouar ULg et al

Poster (2015, January 27)

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See detailIdentification, Design and Evaluation of Pharmacological tools for the orphan GPCR GPR22
Geubelle, Pierre ULg; Gilissen, Julie ULg; Dupuis, Nadine ULg et al

Poster (2015, January 27)

GPCRs are the largest family of membrane receptors and are characterized by 7 transmembrane domains. GPR22 is a GPCR that has no known endogenous ligand and is thus considered "orphan". Its presence ... [more ▼]

GPCRs are the largest family of membrane receptors and are characterized by 7 transmembrane domains. GPR22 is a GPCR that has no known endogenous ligand and is thus considered "orphan". Its presence situated at the heart and brain levels makes it a potential target for new therapeutic pathways. This study consist in the identification of a synthetic ligand of GPR22 receptor to use it as a pharmacological tool in the study of the signaling channels of GPR22 in order to understand its role and to validate it as a new therapeutic target. The initial hypothesis was that GPR22 is coupled to the Gαi protein. [less ▲]

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See detailForskolin-free cAMP assay for Gi-coupled receptors
Gilissen, Julie ULg; Geubelle, Pierre ULg; Dupuis, Nadine ULg et al

in Biochemical Pharmacology (2015)

Detailed reference viewed: 62 (17 ULg)