Jalal Soubhye | Free University of Brussels (original) (raw)

Papers by Jalal Soubhye

Research paper thumbnail of Inhibition of Myeloperoxidase

Handbook of experimental pharmacology, Dec 29, 2020

Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal... more Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. This has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, based on the profound knowledge of structure and function of MPO and its biochemical and biophysical differences with the other homologous human peroxidases, various rational and high-throughput screening attempts were performed in developing specific irreversible and reversible inhibitors. The most prominent candidates as well as MPO inhibitors already studied in clinical trials are introduced and discussed.

Research paper thumbnail of La 17ß-hydroxysteroïde déshydrogénase de type 2 comme cible pour le traitement de l’ostéoporose

info:eu-repo/semantics/publishe

Research paper thumbnail of Rational drug design approach of myeloperoxidase inhibitors using virtual screening

info:eu-repo/semantics/nonPublishe

Research paper thumbnail of Synthèse et évaluation pharmacologique de nouveaux inhibiteurs de la myéloperoxydase dérivés de la 5-fluorotryptamine

info:eu-repo/semantics/nonPublishe

Research paper thumbnail of Native glycosylation and binding of the antidepressant paroxetine in a low-resolution crystal structure of human myeloperoxidase

Acta Crystallographica Section D Structural Biology

Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such p... more Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such plays an essential role in cell-component synthesis, in metabolic and elimination pathways, and in the front-line defence against pathogens. Moreover, MPO is increasingly being reported to play a role in inflammation. The enzymatic activity of MPO has also been shown to depend on its glycosylation. Mammalian MPO crystal structures deposited in the Protein Data Bank (PDB) present only a partial identification of their glycosylation. Here, a newly obtained crystal structure of MPO containing four disulfide-linked dimers and showing an elaborate collection of glycans is reported. These are compared with the glycans identified in proteomics studies and from 18 human MPO structures available in the PDB. The crystal structure also contains bound paroxetine, a blocker of serotonin reuptake that has previously been identified as an irreversible inhibitor of MPO, in the presence of thiocyanate, a ...

Research paper thumbnail of Ornithine Lipid Activates Both TLR4 and the non-canonical NLRP3 Inflammasome

Toll-like receptors (TLRs) are proteins that act as the sentinels of mammalian cells by detecting... more Toll-like receptors (TLRs) are proteins that act as the sentinels of mammalian cells by detecting bacteria and viruses motifs such as the phospholipid lipopolysaccharides (LPS) from Gram-negative bacterial membrane, among others. Bacteria like Vibrio cholerae, when grow in phosphate-depleted medium are unable to produce LPS and other phospholipids and therefore increase the synthesis of ornithine lipids (OLs) to keep membrane integrity and survival. We found that, although the huge structural differences between OL and LPS, our immune system is still able to detect OL and trigger immune response through TLR4 and the non-canonical Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) inflammasome. Similar to LPS, OL induced TLR4-dependent tumor necrosis factor (TNF)-α secretion and Nuclear Factor (NF)-κB activation and therefore also elicited the priming of the NLRP3 inflammasome. Moreover, incubation of macrophages with OL causes caspase-dependent clea...

Research paper thumbnail of CCDC 962082: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Article Characterization and Antioxidant Properties of Six Algerian Propolis Extracts: Ethyl Acetate Extracts Inhibit Myeloperoxidase Activity

Abstract: Because propolis contains many types of antioxidant compounds such as polyphenols and f... more Abstract: Because propolis contains many types of antioxidant compounds such as polyphenols and flavonoids, it can be useful in preventing oxidative damages. Ethyl acetate extracts of propolis from several Algerian regions show high activity by scavenging free radicals, preventing lipid peroxidation and inhibiting myeloperoxidase (MPO). By fractioning and assaying ethyl acetate extracts, it was observed that both polyphenols and flavonoids contribute to these activities. A correlation was observed between the polyphenol content and the MPO inhibition. However, it seems that kaempferol, a flavonoid, contributes mainly to the MPO inhibition. This molecule is in a high amount in the ethyl acetate extract and demonstrates the best efficiency towards the enzyme with an

Research paper thumbnail of Rational design of myeloperoxidase inhibitors using Structure-based virtual screening

Research paper thumbnail of Rational drug design of myeloperoxidase inhibitor using Structure-based virtual screening

info:eu-repo/semantics/nonPublishe

Research paper thumbnail of 三重刺激は微細調整可能な磁気応答を有する応答性重合体【Powered by NICT】

Research paper thumbnail of Preparation of 3-alkyl-5-fluoroindole derivatives as myeloperoxidase inhibitors

Research paper thumbnail of Design, synthesis and study of myeloperoxidase inhibitors in the series of 3-alkylindole

The deleterious effects of MPO make it a new target for medicinal research. The aim of our study ... more The deleterious effects of MPO make it a new target for medicinal research. The aim of our study is to find promising inhibitors of MPO for using them as starting point of new anti-inflammatory drugs. Depending on previous researches on MPO inhibitors, we selected 5-fluorotryptamine as starting compounds. Using docking experiments, we designed a series of compounds derived from 5-fluorotryptamine. Two modifications were proposed: \

Research paper thumbnail of Ligand-based pharmacophore modeling and virtual screening for the discovery of novel myeloperoxidase inhibitors

Research paper thumbnail of Oxidative Stress and Antioxidants

This book illustrates the mechanism of free radicals generation. All the defense lines against th... more This book illustrates the mechanism of free radicals generation. All the defense lines against the oxidative stress including enzymes, endogenous and exogenous molecules are discussed in this Book. Each enzyme, protein and non-protein molecule has a comprehensive description. Tables summarize common foods with the most antioxidants effects and biomarkers of oxidative stress are added as appendixes.

Research paper thumbnail of Synthesis and structire activity relationship of 5-fluorotryptamine analogs as myeloperoxidase inhibitors

Research paper thumbnail of Arylalkylamine Derivatives as Myeloperoxidase Inhibitors, Synthesis and Pharmacological Activity

Proceedings of 1st International Electronic Conference on Medicinal Chemistry, 2015

Myeloperoxidase (MPO) is an important target for drug design because of its contributing role in ... more Myeloperoxidase (MPO) is an important target for drug design because of its contributing role in many inflammatory syndromes such as atherosclerosis, rheumatoid arthritis, end-stage renal disease or neurodegeneration. Rational drug design assisted by virtual screening is an interesting tool to design new chemical entities that could inhibit MPO. After a high throughput virtual screening of a database, bis-2,2′-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol was chosen as a starting hit and we used different strategies of chemical synthesis to perform pharmacomodulation described by the three approaches. This led to 36 compounds that have been assessed in an in vitro inhibition MPO test. We found that the arylalkylamine compounds were active but to a lesser extent than the starting hit. Exception for propylamine derivatives with a phenyl cycle should be noticed. As indolic compounds have demonstrated interesting inhibiting properties, we combined indole ring with the phenolhydropyrimidine structure which led to compounds more active than the hit. Among them, propylamine derivatives were new MPO inhibitors with a nanomolar IC50. Kinetics studies for the most potent inhibitors were conducted and reflected a fast reaction with compound I resulting in the accumulation of compound II Structure-activity.

Research paper thumbnail of Aromatic N-heterocycle derivatives for use as medicine

The invention relates to aromatic N-heterocycle derivatives for use as medicine. In particular, t... more The invention relates to aromatic N-heterocycle derivatives for use as medicine. In particular, the invention refers to aromatic N-heterocycle derivatives for use in the treatment or the prophylaxis of inflammatory diseases or disorders.

Research paper thumbnail of Dual Anti-Inflammatory and Anti-Bacterial Effects of Phenylhydrazide and Phenylhydrazone Derivatives

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through for... more The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to the propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. The implementation of dynamic combinatorial libraries allowed to obtain several compounds derived from aromatic hydrazone with high activity on MPO. These inhibitors were found to be reversible and irreversible MPO inhibitors at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. In vivo evaluation in rats injected by carrageenan showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation. On the other hand,...

Research paper thumbnail of Anti‐inflammatory, antioxidant effects, and bioaccessibility of Tigzirt propolis

Journal of Food Biochemistry

Research paper thumbnail of Inhibition of Myeloperoxidase

Handbook of experimental pharmacology, Dec 29, 2020

Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal... more Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. This has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, based on the profound knowledge of structure and function of MPO and its biochemical and biophysical differences with the other homologous human peroxidases, various rational and high-throughput screening attempts were performed in developing specific irreversible and reversible inhibitors. The most prominent candidates as well as MPO inhibitors already studied in clinical trials are introduced and discussed.

Research paper thumbnail of La 17ß-hydroxysteroïde déshydrogénase de type 2 comme cible pour le traitement de l’ostéoporose

info:eu-repo/semantics/publishe

Research paper thumbnail of Rational drug design approach of myeloperoxidase inhibitors using virtual screening

info:eu-repo/semantics/nonPublishe

Research paper thumbnail of Synthèse et évaluation pharmacologique de nouveaux inhibiteurs de la myéloperoxydase dérivés de la 5-fluorotryptamine

info:eu-repo/semantics/nonPublishe

Research paper thumbnail of Native glycosylation and binding of the antidepressant paroxetine in a low-resolution crystal structure of human myeloperoxidase

Acta Crystallographica Section D Structural Biology

Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such p... more Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such plays an essential role in cell-component synthesis, in metabolic and elimination pathways, and in the front-line defence against pathogens. Moreover, MPO is increasingly being reported to play a role in inflammation. The enzymatic activity of MPO has also been shown to depend on its glycosylation. Mammalian MPO crystal structures deposited in the Protein Data Bank (PDB) present only a partial identification of their glycosylation. Here, a newly obtained crystal structure of MPO containing four disulfide-linked dimers and showing an elaborate collection of glycans is reported. These are compared with the glycans identified in proteomics studies and from 18 human MPO structures available in the PDB. The crystal structure also contains bound paroxetine, a blocker of serotonin reuptake that has previously been identified as an irreversible inhibitor of MPO, in the presence of thiocyanate, a ...

Research paper thumbnail of Ornithine Lipid Activates Both TLR4 and the non-canonical NLRP3 Inflammasome

Toll-like receptors (TLRs) are proteins that act as the sentinels of mammalian cells by detecting... more Toll-like receptors (TLRs) are proteins that act as the sentinels of mammalian cells by detecting bacteria and viruses motifs such as the phospholipid lipopolysaccharides (LPS) from Gram-negative bacterial membrane, among others. Bacteria like Vibrio cholerae, when grow in phosphate-depleted medium are unable to produce LPS and other phospholipids and therefore increase the synthesis of ornithine lipids (OLs) to keep membrane integrity and survival. We found that, although the huge structural differences between OL and LPS, our immune system is still able to detect OL and trigger immune response through TLR4 and the non-canonical Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) inflammasome. Similar to LPS, OL induced TLR4-dependent tumor necrosis factor (TNF)-α secretion and Nuclear Factor (NF)-κB activation and therefore also elicited the priming of the NLRP3 inflammasome. Moreover, incubation of macrophages with OL causes caspase-dependent clea...

Research paper thumbnail of CCDC 962082: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Article Characterization and Antioxidant Properties of Six Algerian Propolis Extracts: Ethyl Acetate Extracts Inhibit Myeloperoxidase Activity

Abstract: Because propolis contains many types of antioxidant compounds such as polyphenols and f... more Abstract: Because propolis contains many types of antioxidant compounds such as polyphenols and flavonoids, it can be useful in preventing oxidative damages. Ethyl acetate extracts of propolis from several Algerian regions show high activity by scavenging free radicals, preventing lipid peroxidation and inhibiting myeloperoxidase (MPO). By fractioning and assaying ethyl acetate extracts, it was observed that both polyphenols and flavonoids contribute to these activities. A correlation was observed between the polyphenol content and the MPO inhibition. However, it seems that kaempferol, a flavonoid, contributes mainly to the MPO inhibition. This molecule is in a high amount in the ethyl acetate extract and demonstrates the best efficiency towards the enzyme with an

Research paper thumbnail of Rational design of myeloperoxidase inhibitors using Structure-based virtual screening

Research paper thumbnail of Rational drug design of myeloperoxidase inhibitor using Structure-based virtual screening

info:eu-repo/semantics/nonPublishe

Research paper thumbnail of 三重刺激は微細調整可能な磁気応答を有する応答性重合体【Powered by NICT】

Research paper thumbnail of Preparation of 3-alkyl-5-fluoroindole derivatives as myeloperoxidase inhibitors

Research paper thumbnail of Design, synthesis and study of myeloperoxidase inhibitors in the series of 3-alkylindole

The deleterious effects of MPO make it a new target for medicinal research. The aim of our study ... more The deleterious effects of MPO make it a new target for medicinal research. The aim of our study is to find promising inhibitors of MPO for using them as starting point of new anti-inflammatory drugs. Depending on previous researches on MPO inhibitors, we selected 5-fluorotryptamine as starting compounds. Using docking experiments, we designed a series of compounds derived from 5-fluorotryptamine. Two modifications were proposed: \

Research paper thumbnail of Ligand-based pharmacophore modeling and virtual screening for the discovery of novel myeloperoxidase inhibitors

Research paper thumbnail of Oxidative Stress and Antioxidants

This book illustrates the mechanism of free radicals generation. All the defense lines against th... more This book illustrates the mechanism of free radicals generation. All the defense lines against the oxidative stress including enzymes, endogenous and exogenous molecules are discussed in this Book. Each enzyme, protein and non-protein molecule has a comprehensive description. Tables summarize common foods with the most antioxidants effects and biomarkers of oxidative stress are added as appendixes.

Research paper thumbnail of Synthesis and structire activity relationship of 5-fluorotryptamine analogs as myeloperoxidase inhibitors

Research paper thumbnail of Arylalkylamine Derivatives as Myeloperoxidase Inhibitors, Synthesis and Pharmacological Activity

Proceedings of 1st International Electronic Conference on Medicinal Chemistry, 2015

Myeloperoxidase (MPO) is an important target for drug design because of its contributing role in ... more Myeloperoxidase (MPO) is an important target for drug design because of its contributing role in many inflammatory syndromes such as atherosclerosis, rheumatoid arthritis, end-stage renal disease or neurodegeneration. Rational drug design assisted by virtual screening is an interesting tool to design new chemical entities that could inhibit MPO. After a high throughput virtual screening of a database, bis-2,2′-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol was chosen as a starting hit and we used different strategies of chemical synthesis to perform pharmacomodulation described by the three approaches. This led to 36 compounds that have been assessed in an in vitro inhibition MPO test. We found that the arylalkylamine compounds were active but to a lesser extent than the starting hit. Exception for propylamine derivatives with a phenyl cycle should be noticed. As indolic compounds have demonstrated interesting inhibiting properties, we combined indole ring with the phenolhydropyrimidine structure which led to compounds more active than the hit. Among them, propylamine derivatives were new MPO inhibitors with a nanomolar IC50. Kinetics studies for the most potent inhibitors were conducted and reflected a fast reaction with compound I resulting in the accumulation of compound II Structure-activity.

Research paper thumbnail of Aromatic N-heterocycle derivatives for use as medicine

The invention relates to aromatic N-heterocycle derivatives for use as medicine. In particular, t... more The invention relates to aromatic N-heterocycle derivatives for use as medicine. In particular, the invention refers to aromatic N-heterocycle derivatives for use in the treatment or the prophylaxis of inflammatory diseases or disorders.

Research paper thumbnail of Dual Anti-Inflammatory and Anti-Bacterial Effects of Phenylhydrazide and Phenylhydrazone Derivatives

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through for... more The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to the propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. The implementation of dynamic combinatorial libraries allowed to obtain several compounds derived from aromatic hydrazone with high activity on MPO. These inhibitors were found to be reversible and irreversible MPO inhibitors at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. In vivo evaluation in rats injected by carrageenan showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation. On the other hand,...

Research paper thumbnail of Anti‐inflammatory, antioxidant effects, and bioaccessibility of Tigzirt propolis

Journal of Food Biochemistry