Fotiadu F

References (7)

Title : Slowing down fat digestion and absorption by an oxadiazolone inhibitor targeting selectively gastric lipolysis - Point_2016_Eur.J.Med.Chem_123_834
Author(s) : Point V , Benarouche A , Zarrillo J , Guy A , Magnez R , Fonseca L , Raux B , Leclaire J , Buono G , Fotiadu F , Durand T , Carriere F , Vaysse C , Couedelo L , Cavalier JF
Ref : Eur Journal of Medicinal Chemistry , 123 :834 , 2016
Abstract : Based on a previous study and in silico molecular docking experiments, we have designed and synthesized a new series of ten 5-Alkoxy-N-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one derivatives (RmPPOX). These molecules were further evaluated as selective and potent inhibitors of mammalian digestive lipases: purified dog gastric lipase (DGL) and guinea pig pancreatic lipase related protein 2 (GPLRP2), as well as porcine (PPL) and human (HPL) pancreatic lipases contained in porcine pancreatic extracts (PPE) and human pancreatic juices (HPJ), respectively. These compounds were found to strongly discriminate classical pancreatic lipases (poorly inhibited) from gastric lipase (fully inhibited). Among them, the 5-(2-(Benzyloxy)ethoxy)-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one (BemPPOX) was identified as the most potent inhibitor of DGL, even more active than the FDA-approved drug Orlistat. BemPPOX and Orlistat were further compared in vitro in the course of test meal digestion, and in vivo with a mesenteric lymph duct cannulated rat model to evaluate their respective impacts on fat absorption. While Orlistat inhibited both gastric and duodenal lipolysis and drastically reduced fat absorption in rats, BemPPOX showed a specific action on gastric lipolysis that slowed down the overall lipolysis process and led to a subsequent reduction of around 55% of the intestinal absorption of fatty acids compared to controls. All these data promote BemPPOX as a potent candidate to efficiently regulate the gastrointestinal lipolysis, and to investigate its link with satiety mechanisms and therefore develop new strategies to "fight against obesity".
ESTHER : Point_2016_Eur.J.Med.Chem_123_834
PubMedSearch : Point_2016_Eur.J.Med.Chem_123_834
PubMedID: 27543878
Gene_locus related to this paper: canfa-1lipg , human-LIPF

Title : Supported inhibitor for fishing lipases in complex biological media and mass spectrometry identification - Delorme_2014_Biochimie_107 Pt A_124
Author(s) : Delorme V , Raux B , Puppo R , Leclaire J , Cavalier JF , Marc S , Kamarajugadda PK , Buono G , Fotiadu F , Canaan S , Carriere F
Ref : Biochimie , 107 Pt A :124 , 2014
Abstract : A synthetic phosphonate inhibitor designed for lipase inhibition but displaying a broader range of activity was covalently immobilized on a solid support to generate a function-directed tool targeting serine hydrolases. To achieve this goal, straightforward and reliable analytical techniques were developed, allowing the monitoring of the solid support's chemical functionalization, enzyme capture processes and physisorption artifacts. This grafted inhibitor was tested on pure lipases and serine proteases from various origins, and assayed for the selective capture of lipases from several complex biological extracts. The direct identification of captured enzymes by mass spectrometry brought the proof of concept on the efficiency of this supported covalent inhibitor. The features and limitations of this "enzyme-fishing" proteomic tool provide new insight on solid-liquid inhibition process.
ESTHER : Delorme_2014_Biochimie_107 Pt A_124
PubMedSearch : Delorme_2014_Biochimie_107 Pt A_124
PubMedID: 25064360

Title : Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones. - Point_2012_Eur.J.Med.Chem_58_452
Author(s) : Point V , Pavan Kumar KV , Marc S , Delorme V , Parsiegla G , Amara S , Carriere F , Buono G , Fotiadu F , Canaan S , Leclaire J , Cavalier JF
Ref : Eur Journal of Medicinal Chemistry , 58 :452 , 2012
Abstract : We report here the reactivity and selectivity of three 5-Methoxy-N-3-Phenyl substituted-1,3,4-Oxadiazol-2(3H)-ones (MPOX, as well as meta and para-PhenoxyPhenyl derivatives, i.e.MmPPOX and MpPPOX) with respect to the inhibition of mammalian digestive lipases: dog gastric lipase (DGL), human (HPL) and porcine (PPL) pancreatic lipases, human (HPLRP2) and guinea pig (GPLRP2) pancreatic lipase-related proteins 2, human pancreatic carboxyl ester hydrolase (hCEH), and porcine pancreatic extracts (PPE). All three oxadiazolones displayed similar inhibitory activities on DGL, PLRP2s and hCEH than the FDA-approved anti-obesity drug Orlistat towards the same enzymes. These compounds appeared however to be discriminative of HPL (poorly inhibited) and PPL (fully inhibited). The inhibitory activities obtained experimentally in vitro were further rationalized using in silico molecular docking. In the case of DGL, we demonstrated that the phenoxy group plays a key role in specific molecular interactions within the lipase's active site. The absence of this group in the case of MPOX, as well as its connectivity to the neighbouring aromatic ring in the case of MmPPOX and MpPPOX, strongly impacts the inhibitory efficiency of these oxadiazolones and leads to a significant gain in selectivity towards the lipases tested. The powerful inhibition of PPL, DGL, PLRP2s, hCEH and to a lesser extend HPL, suggests that oxadiazolone derivatives could also provide useful leads for the development of novel and more discriminative inhibitors of digestive lipases. These inhibitors could be used for a better understanding of individual lipase function as well as for drug development aiming at the regulation of the whole gastrointestinal lipolysis process.
ESTHER : Point_2012_Eur.J.Med.Chem_58_452
PubMedSearch : Point_2012_Eur.J.Med.Chem_58_452
PubMedID: 23153815
Gene_locus related to this paper: canfa-1lipg , cavpo-2plrp , human-CEL , human-PNLIP , human-PNLIPRP2 , pig-1plip

Title : MmPPOX inhibits Mycobacterium tuberculosis lipolytic enzymes belonging to the hormone-sensitive lipase family and alters mycobacterial growth - Delorme_2012_PLoS.One_7_e46493
Author(s) : Delorme V , Diomande SV , Dedieu L , Cavalier JF , Carriere F , Kremer L , Leclaire J , Fotiadu F , Canaan S
Ref : PLoS ONE , 7 :e46493 , 2012
Abstract : Lipid metabolism plays an important role during the lifetime of Mycobacterium tuberculosis, the causative agent of tuberculosis. Although M. tuberculosis possesses numerous lipolytic enzymes, very few have been characterized yet at a biochemical/pharmacological level. This study was devoted to the M. tuberculosis lipolytic enzymes belonging to the Hormone-Sensitive Lipase (HSL) family, which encompasses twelve serine hydrolases closely related to the human HSL. Among them, nine were expressed, purified and biochemically characterized using a broad range of substrates. In vitro enzymatic inhibition studies using the recombinant HSL proteins, combined with mass spectrometry analyses, revealed the potent inhibitory activity of an oxadiazolone compound, named MmPPOX. In addition, we provide evidence that MmPPOX alters mycobacterial growth. Overall, these findings suggest that the M. tuberculosis HSL family displays important metabolic functions, thus opening the way to further investigations linking the involvement of these enzymes in mycobacterial growth.
ESTHER : Delorme_2012_PLoS.One_7_e46493
PubMedSearch : Delorme_2012_PLoS.One_7_e46493
PubMedID: 23029536
Gene_locus related to this paper: myctu-Rv2970c

Title : Effects of surfactants on lipase structure, activity, and inhibition - Delorme_2011_Pharm.Res_28_1831
Author(s) : Delorme V , Dhouib R , Canaan S , Fotiadu F , Carriere F , Cavalier JF
Ref : Pharm Res , 28 :1831 , 2011
Abstract : Lipase inhibitors are the main anti-obesity drugs prescribed these days, but the complexity of their mechanism of action is making it difficult to develop new molecules for this purpose. The efficacy of these drugs is known to depend closely on the physico-chemistry of the lipid-water interfaces involved and on the unconventional behavior of the lipases which are their target enzymes. The lipolysis reaction which occurs at an oil-water interface involves complex equilibria between adsorption-desorption processes, conformational changes and catalytic mechanisms. In this context, surfactants can induce significant changes in the partitioning of the enzyme and the inhibitor between the water phase and lipid-water interfaces. Surfactants can be found at the oil-water interface where they compete with lipases for adsorption, but also in solution in the form of micellar aggregates and monomers that may interact with hydrophobic parts of lipases in solution. These various interactions, combined with the emulsification and dispersion of insoluble substrates and inhibitors, can either promote or decrease the activity and the inhibition of lipases. Here, we review some examples of the various effects of surfactants on lipase structure, activity and inhibition, which show how complex the various equilibria involved in the lipolysis reaction tend to be.
ESTHER : Delorme_2011_Pharm.Res_28_1831
PubMedSearch : Delorme_2011_Pharm.Res_28_1831
PubMedID: 21234659

Title : In vitro stereoselective hydrolysis of diacylglycerols by hormone-sensitive lipase - Rodriguez_2010_Biochim.Biophys.Acta_1801_77
Author(s) : Rodriguez JA , Ben Ali Y , Abdelkafi S , Mendoza LD , Leclaire J , Fotiadu F , Buono G , Carriere F , Abousalham A
Ref : Biochimica & Biophysica Acta , 1801 :77 , 2010
Abstract : Hormone-sensitive lipase (HSL) contributes importantly to the mobilization of fatty acids in adipocytes and shows a substrate preference for the diacylglycerols (DAGs) originating from triacylglycerols. To determine whether HSL shows any stereopreference during the hydrolysis of diacylglycerols, racemic 1,2(2,3)-sn-diolein was used as a substrate and the enantiomeric excess (ee%) of residual 1,2-sn-diolein over 2,3-sn-diolein was measured as a function of DAG hydrolysis. Enantiomeric DAGs were separated by performing chiral-stationary-phase HPLC after direct derivatization from lipolysis product extracts. The fact that the ee% of 1,2-sn-diolein over 2,3-sn-diolein increased with the level of hydrolysis indicated that HSL has a preference for 2,3-sn-diolein as a substrate and therefore a stereopreference for the sn-3 position of dioleoylglycerol. The ee% of 1,2-sn-diolein reached a maximum value of 36% at 42% hydrolysis. Among the various mammalian lipases tested so far, HSL is the only lipolytic carboxylester hydrolase found to have a pronounced stereospecificity for the sn-3 position of dioleoylglycerol.
ESTHER : Rodriguez_2010_Biochim.Biophys.Acta_1801_77
PubMedSearch : Rodriguez_2010_Biochim.Biophys.Acta_1801_77
PubMedID: 19800417

Title : Novel chromatographic resolution of chiral diacylglycerols and analysis of the stereoselective hydrolysis of triacylglycerols by lipases - Rodriguez_2008_Anal.Biochem_375_196
Author(s) : Rodriguez JA , Mendoza LD , Pezzotti F , Vanthuyne N , Leclaire J , Verger R , Buono G , Carriere F , Fotiadu F
Ref : Analytical Biochemistry , 375 :196 , 2008
Abstract : In the present study, we propose a general and accessible method for the resolution of enantiomeric 1,2-sn- and 2,3-sn-diacylglycerols based on derivatization by isocyanates, which can be easily used routinely by biochemists to evaluate the stereopreferences of lipases in a time course of triacylglycerol (TAG) hydrolysis. Diacylglycerol (DAG) enantiomers were transformed into carbamates using achiral and commercially available reagents. Excellent separation and resolution factors were obtained for diacylglycerols present in lipolysis reaction mixtures. This analytical method was then applied to investigate the stereoselectivity of three model lipases (porcine pancreatic lipase, PPL; lipase from Rhizomucor miehei, MML; and recombinant dog gastric lipase, rDGL) in the time course of hydrolysis of prochiral triolein as a substrate. From the measurements of the diglyceride enantiomeric excess it was confirmed that PPL was not stereospecific (position sn-1 vs sn-3 of triolein), whereas MML and rDGL preferentially hydrolyzed the ester bond at position sn-1 and sn-3, respectively. The enantiomeric excess of DAGs was not constant with time, decreasing with the course of hydrolysis. This was due to the fact that DAGs can be products of the stereospecific hydrolysis of TAGs and substrates for stereospecific hydrolysis into monoacylglycerols.
ESTHER : Rodriguez_2008_Anal.Biochem_375_196
PubMedSearch : Rodriguez_2008_Anal.Biochem_375_196
PubMedID: 18162167