Erika Bourguet | Université de Reims Champagne-Ardenne (original) (raw)
Papers by Erika Bourguet
HAL (Le Centre pour la Communication Scientifique Directe), 2007
REIMS-BU Santé (514542104) / SudocSudocFranceF
Journal of Medicinal Chemistry, 2022
This Perspective describes the classification, structures, substrates, mechanisms of action, and ... more This Perspective describes the classification, structures, substrates, mechanisms of action, and implications of human neuraminidases (hNEUs) in various pathologies. Some inhibitors have been developed for each isoform, leading to more precise interactions with hNEUs. Although crystal structure data are available for NEU2, most of the findings are based on NEU1 inhibition, and limited information is available for other hNEUs. Therefore, the synthesis of new compounds would facilitate the enrichment of the arsenal of inhibitors to better understand the roles of hNEUs and their mechanisms of action. Nevertheless, due to the already known inhibitors of human neuraminidase enzymes, a structure-activity relationship is presented along with different approaches to inhibit these enzymes for the development of potent and selective inhibitors. Among the different emerging strategies, one is the inhibition of the dimerization of NEU1 or NEU3, and the second is the inhibition of certain receptors located close to hNEU.
Advances in Cancer Drug Targets, 2016
Objectives: Unrestrained proteolytic activity constitutes the hallmark of inflammatory response a... more Objectives: Unrestrained proteolytic activity constitutes the hallmark of inflammatory response as periodontal diseases. Proteases involved belong mainly to the serine- and metallo-peptidase families. Elevated levels of serine proteases as leukocyte elastase (HLE) and plasmin together with several metalloproteinases (MMPs) including collagenases i.e. MMP-1, MMP-13, gelatinases i.e. MMP-2, MMP-9, and stromelysins i.e. MMP-3, can be identified in periodontal diseases. Serine proteases are the major inducers of proMMP activation creating a local environment with excess of matrix proteolytic activity. Inhibitory substances that can disrupt this degradation cascade may be considered as an effective therapy against periodontal diseases. Methods: Long chain unsaturated fatty acids, as oleic acid was reported to interfere with the activity of enzyme systems. Thus, we modified galardin®, a broad spectrum MMP inhibitor, at P’2 position with oleic acid and studied the properties of these deriv...
Biochemical Pharmacology, 2011
Molecular modeling was undertaken at aims to analyze the interactions between oleic acid and huma... more Molecular modeling was undertaken at aims to analyze the interactions between oleic acid and human leukocyte elastase (HLE), plasmin and matrix metalloproteinase-2 (MMP-2), involved in the inhibitory capacity of fatty acid towards those proteases. The carboxylic acid group of the fatty acid was found to form a salt bridge with Arg 217 of HLE while unsaturation interacted with Phe 192 and Val 216 at the S 3 subsite, and alkyl end group occupied S 1 subsite. In keeping with the main contribution of kringle 5 domain in plasmin-oleic acid interaction [Huet E et al. Biochem Pharmacol 2004;67(4):643-54], docking computations revealed that the long alkyl chain of fatty acid inserted within an hydrophobic groove of this domain with the carboxylate forming a salt bridge with Arg 512. Finally, blind docking revealed that oleic acid could occupy both S 0 1 subsite and Fn(II) 3 domain of MMP-2. Several residues involved in Fn(II) 3 / oleic acid interaction were similarly implicated in binding of this domain to collagen. Oleic acid was covalently linked to galardin (at P 0 2 position): OL-GAL (CONHOH) or to its carboxylic acid counterpart: OL-GAL (COOH), with the idea to obtain potent MMP inhibitors able to also interfere with elastase and plasmin activity. OL-GALs were found less potent MMP inhibitors as compared to galardin and no selectivity for MMP-2 or MMP-9 could be demonstrated. Docking computations indicated that contrary to oleic acid, OL-GAL binds only to MMP-2 active site and surprisingly, hydroxamic acid was unable to chelate Zn, but instead forms a salt bridge with the N-terminal Tyr 110. Interestingly, oleic acid and particularly OL-GALs proved to potently inhibit MMP-13. OL-GAL was found as potent as galardin (K i equal to 1.8 nM for OL-GAL and 1.45 nM for GAL) and selectivity for that MMP was attained (2-3 log orders of difference in inhibitory potency as compared to other MMPs). Molecular modeling studies indicated that oleic acid could be accommodated within S 0 1 pocket of MMP-13 with carboxylic acid chelating Zn ion. OL-GAL also occupied such pocket but hydroxamic acid did not interact with Zn but instead was located at 2.8 Å from Tyr 176. Since these derivatives retained, as their oleic acid original counterpart, the capacity to inhibit the amidolytic activity of HLE and plasmin as well as to decrease HLE-and plasmin-mediated pro MMP-3 activation, they might be of therapeutic value to control proteolytic cascades in chronic inflammatory disorders.
Anti-Cancer Agents in Medicinal Chemistry, 2012
Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary... more Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named "LipoGalardin" (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.
C R Chim, 2006
« Quelle chimie organique demain ? » Cet article présente les conclusions de la première édition ... more « Quelle chimie organique demain ? » Cet article présente les conclusions de la première édition des entretiens de synthèse organique et de prospective (ESYOP), dont l'objectif était d'apporter une réponse collective à cette question fondamentale. Les défis mis en évidence par une trentaine de jeunes chercheurs francophones de la génération 30–39 ans peuvent se regrouper suivant trois thèmes interdépendants : la conquête du simple, la nature comme guide et la conception d'édifices moléculaires capables d'autonomie et d'adaptabilité. Le visage de la chimie organique de demain sera peut-être celui d'une science cherchant à construire avec une grande économie de moyens des systèmes moléculaires inspirés de la nature et dotés d'une forme d'intelligence. Pour citer cet article : P. Compain et al., C. R. Chimie 9 (2006).Future alchemy: account of the ESYOP experiment. “Organic Chemistry, where now?” This article reports the outcome of the first edition of ESYOP, a symposium devoted to the future of organic chemistry. The collective answer proposed to the above question has been elaborated by thirty-year-old French-speaking researchers. The challenges reported may be structured in three interdependent themes: quest for simplicity, nature as a guide, design of molecular structures capable of autonomy and adaptability. In the future, organic chemistry may be a science devoted to the synthesis of ‘intelligent’ molecular systems inspired by Nature by using the simplest means. To cite this article: P. Compain et al., C. R. Chimie 9 (2006).
This review summarizes key literature defining the phenotypes of individual class IIa HDAC protei... more This review summarizes key literature defining the phenotypes of individual class IIa HDAC proteins and compounds that selectively target their enzymatic catalytic domain (CD). The focus is on the effects of class IIa HDACs in physiological and pathological conditions, both in vitro and in vivo, and their mode of action in regulating genes, upstream proteins and signaling pathways. Phenotype studies further demonstrate either beneficial or detrimental effects of silencing selected class IIa HDACs or their enzymatic properties. We also summarize the knowledge gained from structure-activity relationships of CD inhibitors as well as molecular mechanisms underpinning isozyme selectivity where crystal structures or modelling studies were available. Given that the numbers of genes affected by silencing class IIa HDACs are much smaller than class I, the role of gene regulation of class IIa HDACs could be much more selective. Since class IIa HDACs have restricted tissue distributions and mu...
Future Medicinal Chemistry
Finding HDAC activator opens new therapeutic perspectives in pathologies in which HDACs have been... more Finding HDAC activator opens new therapeutic perspectives in pathologies in which HDACs have been suggested to be downregulated. "
Biologie aujourd'hui, 2017
Alcohol use disorder is a devastating illness with a profound health impact, and its development ... more Alcohol use disorder is a devastating illness with a profound health impact, and its development is dependent on both genetic and environmental factors. This disease occurs over time and requires changes in brain gene expression. There is converging evidence suggesting that the epigenetic processes may play a role in the alcohol-induced gene regulations and behavior such as the intervention of DNA methylation and histone acetylation. Histone acetylation, like histone methylation, is a highly dynamic process regulated by two classes of enzymes: histone acetyltransferases and histone deacetylases (HDACs). To date, 18 human HDAC isoforms have been characterized, and based on their sequence homologies and cofactor dependencies, they have been phylogenetically categorized into 4 main classes: classes I, II (a and b), III, and IV. In the brain, expression of the different classes of HDACs varies between cell types and also in their subcellular localization (nucleus and/or cytosol). Furthe...
Journal of medicinal chemistry, Jan 3, 2017
Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapi... more Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.
Bioconjugate Chemistry, 2016
The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the u... more The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the understanding of the roles of MMPs in different diseases. Most MMP probes designed are fluorogenic substrates, often suffering from photo- and chemical instability and providing a fluorescence signal of moderate intensity, which is difficult to detect and analyze when dealing with crude biological samples. Here, an inhibitor that inhibits MMP-2 more selectively than Galardin has been synthesized and used for enzyme labeling and detection of the MMP-2 activity. A complete MMP-2 recognition complex consisting of a biotinylated MMP inhibitor tagged with the streptavidin-quantum dot (QD) conjugate has been prepared. This recognition complex, which is characterized by a narrow fluorescence emission spectrum, long fluorescence lifetime, and negligible photobleaching, has been demonstrated to specifically detect MMP-2 in in vitro sandwich-type biochemical assays with sensitivities orders of magnitude higher than those of the existing gold standards employing organic dyes. The approach developed can be used for specific in vitro visualization and testing of MMP-2 in cells and tissues with sensitivities significantly exceeding those of the best existing fluorogenic techniques.
HAL (Le Centre pour la Communication Scientifique Directe), 2007
REIMS-BU Santé (514542104) / SudocSudocFranceF
Journal of Medicinal Chemistry, 2022
This Perspective describes the classification, structures, substrates, mechanisms of action, and ... more This Perspective describes the classification, structures, substrates, mechanisms of action, and implications of human neuraminidases (hNEUs) in various pathologies. Some inhibitors have been developed for each isoform, leading to more precise interactions with hNEUs. Although crystal structure data are available for NEU2, most of the findings are based on NEU1 inhibition, and limited information is available for other hNEUs. Therefore, the synthesis of new compounds would facilitate the enrichment of the arsenal of inhibitors to better understand the roles of hNEUs and their mechanisms of action. Nevertheless, due to the already known inhibitors of human neuraminidase enzymes, a structure-activity relationship is presented along with different approaches to inhibit these enzymes for the development of potent and selective inhibitors. Among the different emerging strategies, one is the inhibition of the dimerization of NEU1 or NEU3, and the second is the inhibition of certain receptors located close to hNEU.
Advances in Cancer Drug Targets, 2016
Objectives: Unrestrained proteolytic activity constitutes the hallmark of inflammatory response a... more Objectives: Unrestrained proteolytic activity constitutes the hallmark of inflammatory response as periodontal diseases. Proteases involved belong mainly to the serine- and metallo-peptidase families. Elevated levels of serine proteases as leukocyte elastase (HLE) and plasmin together with several metalloproteinases (MMPs) including collagenases i.e. MMP-1, MMP-13, gelatinases i.e. MMP-2, MMP-9, and stromelysins i.e. MMP-3, can be identified in periodontal diseases. Serine proteases are the major inducers of proMMP activation creating a local environment with excess of matrix proteolytic activity. Inhibitory substances that can disrupt this degradation cascade may be considered as an effective therapy against periodontal diseases. Methods: Long chain unsaturated fatty acids, as oleic acid was reported to interfere with the activity of enzyme systems. Thus, we modified galardin®, a broad spectrum MMP inhibitor, at P’2 position with oleic acid and studied the properties of these deriv...
Biochemical Pharmacology, 2011
Molecular modeling was undertaken at aims to analyze the interactions between oleic acid and huma... more Molecular modeling was undertaken at aims to analyze the interactions between oleic acid and human leukocyte elastase (HLE), plasmin and matrix metalloproteinase-2 (MMP-2), involved in the inhibitory capacity of fatty acid towards those proteases. The carboxylic acid group of the fatty acid was found to form a salt bridge with Arg 217 of HLE while unsaturation interacted with Phe 192 and Val 216 at the S 3 subsite, and alkyl end group occupied S 1 subsite. In keeping with the main contribution of kringle 5 domain in plasmin-oleic acid interaction [Huet E et al. Biochem Pharmacol 2004;67(4):643-54], docking computations revealed that the long alkyl chain of fatty acid inserted within an hydrophobic groove of this domain with the carboxylate forming a salt bridge with Arg 512. Finally, blind docking revealed that oleic acid could occupy both S 0 1 subsite and Fn(II) 3 domain of MMP-2. Several residues involved in Fn(II) 3 / oleic acid interaction were similarly implicated in binding of this domain to collagen. Oleic acid was covalently linked to galardin (at P 0 2 position): OL-GAL (CONHOH) or to its carboxylic acid counterpart: OL-GAL (COOH), with the idea to obtain potent MMP inhibitors able to also interfere with elastase and plasmin activity. OL-GALs were found less potent MMP inhibitors as compared to galardin and no selectivity for MMP-2 or MMP-9 could be demonstrated. Docking computations indicated that contrary to oleic acid, OL-GAL binds only to MMP-2 active site and surprisingly, hydroxamic acid was unable to chelate Zn, but instead forms a salt bridge with the N-terminal Tyr 110. Interestingly, oleic acid and particularly OL-GALs proved to potently inhibit MMP-13. OL-GAL was found as potent as galardin (K i equal to 1.8 nM for OL-GAL and 1.45 nM for GAL) and selectivity for that MMP was attained (2-3 log orders of difference in inhibitory potency as compared to other MMPs). Molecular modeling studies indicated that oleic acid could be accommodated within S 0 1 pocket of MMP-13 with carboxylic acid chelating Zn ion. OL-GAL also occupied such pocket but hydroxamic acid did not interact with Zn but instead was located at 2.8 Å from Tyr 176. Since these derivatives retained, as their oleic acid original counterpart, the capacity to inhibit the amidolytic activity of HLE and plasmin as well as to decrease HLE-and plasmin-mediated pro MMP-3 activation, they might be of therapeutic value to control proteolytic cascades in chronic inflammatory disorders.
Anti-Cancer Agents in Medicinal Chemistry, 2012
Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary... more Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named "LipoGalardin" (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.
C R Chim, 2006
« Quelle chimie organique demain ? » Cet article présente les conclusions de la première édition ... more « Quelle chimie organique demain ? » Cet article présente les conclusions de la première édition des entretiens de synthèse organique et de prospective (ESYOP), dont l'objectif était d'apporter une réponse collective à cette question fondamentale. Les défis mis en évidence par une trentaine de jeunes chercheurs francophones de la génération 30–39 ans peuvent se regrouper suivant trois thèmes interdépendants : la conquête du simple, la nature comme guide et la conception d'édifices moléculaires capables d'autonomie et d'adaptabilité. Le visage de la chimie organique de demain sera peut-être celui d'une science cherchant à construire avec une grande économie de moyens des systèmes moléculaires inspirés de la nature et dotés d'une forme d'intelligence. Pour citer cet article : P. Compain et al., C. R. Chimie 9 (2006).Future alchemy: account of the ESYOP experiment. “Organic Chemistry, where now?” This article reports the outcome of the first edition of ESYOP, a symposium devoted to the future of organic chemistry. The collective answer proposed to the above question has been elaborated by thirty-year-old French-speaking researchers. The challenges reported may be structured in three interdependent themes: quest for simplicity, nature as a guide, design of molecular structures capable of autonomy and adaptability. In the future, organic chemistry may be a science devoted to the synthesis of ‘intelligent’ molecular systems inspired by Nature by using the simplest means. To cite this article: P. Compain et al., C. R. Chimie 9 (2006).
This review summarizes key literature defining the phenotypes of individual class IIa HDAC protei... more This review summarizes key literature defining the phenotypes of individual class IIa HDAC proteins and compounds that selectively target their enzymatic catalytic domain (CD). The focus is on the effects of class IIa HDACs in physiological and pathological conditions, both in vitro and in vivo, and their mode of action in regulating genes, upstream proteins and signaling pathways. Phenotype studies further demonstrate either beneficial or detrimental effects of silencing selected class IIa HDACs or their enzymatic properties. We also summarize the knowledge gained from structure-activity relationships of CD inhibitors as well as molecular mechanisms underpinning isozyme selectivity where crystal structures or modelling studies were available. Given that the numbers of genes affected by silencing class IIa HDACs are much smaller than class I, the role of gene regulation of class IIa HDACs could be much more selective. Since class IIa HDACs have restricted tissue distributions and mu...
Future Medicinal Chemistry
Finding HDAC activator opens new therapeutic perspectives in pathologies in which HDACs have been... more Finding HDAC activator opens new therapeutic perspectives in pathologies in which HDACs have been suggested to be downregulated. "
Biologie aujourd'hui, 2017
Alcohol use disorder is a devastating illness with a profound health impact, and its development ... more Alcohol use disorder is a devastating illness with a profound health impact, and its development is dependent on both genetic and environmental factors. This disease occurs over time and requires changes in brain gene expression. There is converging evidence suggesting that the epigenetic processes may play a role in the alcohol-induced gene regulations and behavior such as the intervention of DNA methylation and histone acetylation. Histone acetylation, like histone methylation, is a highly dynamic process regulated by two classes of enzymes: histone acetyltransferases and histone deacetylases (HDACs). To date, 18 human HDAC isoforms have been characterized, and based on their sequence homologies and cofactor dependencies, they have been phylogenetically categorized into 4 main classes: classes I, II (a and b), III, and IV. In the brain, expression of the different classes of HDACs varies between cell types and also in their subcellular localization (nucleus and/or cytosol). Furthe...
Journal of medicinal chemistry, Jan 3, 2017
Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapi... more Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.
Bioconjugate Chemistry, 2016
The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the u... more The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the understanding of the roles of MMPs in different diseases. Most MMP probes designed are fluorogenic substrates, often suffering from photo- and chemical instability and providing a fluorescence signal of moderate intensity, which is difficult to detect and analyze when dealing with crude biological samples. Here, an inhibitor that inhibits MMP-2 more selectively than Galardin has been synthesized and used for enzyme labeling and detection of the MMP-2 activity. A complete MMP-2 recognition complex consisting of a biotinylated MMP inhibitor tagged with the streptavidin-quantum dot (QD) conjugate has been prepared. This recognition complex, which is characterized by a narrow fluorescence emission spectrum, long fluorescence lifetime, and negligible photobleaching, has been demonstrated to specifically detect MMP-2 in in vitro sandwich-type biochemical assays with sensitivities orders of magnitude higher than those of the existing gold standards employing organic dyes. The approach developed can be used for specific in vitro visualization and testing of MMP-2 in cells and tissues with sensitivities significantly exceeding those of the best existing fluorogenic techniques.