Renard PY


Full name : Renard Pierre-Yves

First name : Pierre-Yves

Mail : University of Rouen\; UMR 6014 CNRS COBRA\; Bioorganic chemistry team\; IRCOF rue Tesniere\; Mont-Saint-Aignan\; 76130

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Country : France

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Phone : +33235522476

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References (36)

Title : Detoxification of V-nerve agents assisted by a microperoxidase: new pathway revealed by the use of a relevant VX simulant - Baptista_2024_Chembiochem__e202400137
Author(s) : Baptista da Silva V , Mahy JP , Brazzolotto X , Renard PY , Ricoux R , Legros J
Ref : Chembiochem , :e202400137 , 2024
Abstract : The biocatalyzed oxidative detoxification of the V-series simulant PhX, by mean of the microperoxidase AcMP11, affords the corresponding phosphonothioate as the prominent product instead of the classical P-S and P-O bond cleavage. While PhX is structurally very close to the live agent VX (the methyl group is replaced by a phenyl), assessment with other surrogates missing the nucleophilic amino function displayed more resistance under the same conditions with no phosphonothioate observed. These encouraging results highlight 1) the efficacy of AcMP11 microperoxidase to efficiently detoxify V-series organophosphorus nerve agents (OPNA), and 2) the necessity to use representative alkyl or aryl phosphonothioates simulants such as PhX bearing the appropriate side chain as well as the P-O and P-S cleavable bond to mimic accurately the V-series OPNA to prevent false positive or false negative results.
ESTHER : Baptista_2024_Chembiochem__e202400137
PubMedSearch : Baptista_2024_Chembiochem__e202400137
PubMedID: 38591336

Title : A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning - Da Silva_2022_J.Med.Chem_65_4649
Author(s) : Da Silva O , Probst N , Landry C , Hanak AS , Warnault P , Coisne C , Calas AG , Gosselet F , Courageux C , Gastellier AJ , Trancart M , Baati R , Dehouck MP , Jean L , Nachon F , Renard PY , Dias J
Ref : Journal of Medicinal Chemistry , 65 :4649 , 2022
Abstract : Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their in vitro reactivation efficacy on inhibited human acetylcholinesterase, the crystal structure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics. We then evaluated their endothelial permeability coefficients with a human in vitro model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood-brain barrier.
ESTHER : Da Silva_2022_J.Med.Chem_65_4649
PubMedSearch : Da Silva_2022_J.Med.Chem_65_4649
PubMedID: 35255209
Gene_locus related to this paper: human-ACHE

Title : Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP\/PS1 Mice - Viayna_2021_J.Med.Chem_64_812
Author(s) : Viayna E , Coquelle N , Cieslikiewicz-Bouet M , Cisternas P , Oliva CA , Sanchez-Lopez E , Ettcheto M , Bartolini M , De Simone A , Ricchini M , Rendina M , Pons M , Firuzi O , Perez B , Saso L , Andrisano V , Nachon F , Brazzolotto X , Garcia ML , Camins A , Silman I , Jean L , Inestrosa NC , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 64 :812 , 2021
Abstract : The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
ESTHER : Viayna_2021_J.Med.Chem_64_812
PubMedSearch : Viayna_2021_J.Med.Chem_64_812
PubMedID: 33356266
Gene_locus related to this paper: human-ACHE

Title : Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor - Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
Author(s) : Cieslikiewicz-Bouet M , Naldi M , Bartolini M , Perez B , Servent D , Jean L , Araoz R , Renard PY
Ref : Biochemical Pharmacology , :114010 , 2020
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder associated with cholinergic dysfunction, provoking memory loss and cognitive dysfunction in elderly patients. The cholinergic hypothesis provided over the years with molecular targets for developing palliative treatments for AD, acting on the cholinergic system, namely, acetylcholinesterase and alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). In our synthetic work, we used "click-chemistry" to synthesize two Multi Target Directed Ligands (MTDLs) MB105 and MB118 carrying tacrine and quinuclidine scaffolds which are known for their anticholinesterase and alpha7 nicotinic acetylcholine receptor agonist activities, respectively. Both, MB105 and MB118, inhibit human acetylcholinesterase and human butyrylcholinesterase in the nanomolar range. Electrophysiological recordings on Xenopus laevis oocytes expressing human alpha7 nAChR showed that MB105 and MB118 acted as partial agonists of the referred nicotinic receptor, albeit, with different potencies despite their similar structure. The different substitution at C-3 on the 2,3-disubtituted quinuclidine scaffold may account for the significantly lower potency of MB118 compared to MB105. Electrophysiological recordings showed that the tacrine precursor MB320 behaved as a competitive antagonist of human alpha7 nAChR, in the micromolar range, while the quinuclidine synthetic precursor MB099 acted as a partial agonist. Taken all together, MB105 behaved as a partial agonist of alpha7 nAChR at concentrations where it completely inhibited human acetylcholinesterase activity paving the way for the design of novel MTDLs for palliative treatment of AD.
ESTHER : Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
PubMedSearch : Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
PubMedID: 32360492

Title : Pharmacokinetic evaluation of brain penetrating morpholine-3-hydroxy-2-pyridine oxime as an antidote for nerve agent poisoning - Zorbaz_2020_ACS.Chem.Neurosci__
Author(s) : Zorbaz T , Misetic P , Probst N , Zunec S , Zandona A , Mendas G , Micek V , Macek Hrvat N , Katalinic M , Braiki A , Jean L , Renard PY , Gabelica Markovic V , Kovarik Z
Ref : ACS Chem Neurosci , : , 2020
Abstract : Nerve agents, the deadliest chemical warfare agents, are potent inhibitors of acetylcholinesterase (AChE) and cause rapid cholinergic crisis with serious symptoms of poisoning. Oxime reactivators of AChE are used in medical practice in treatment of nerve agent poisoning, but the search for novel improved reactivators with central activity is an ongoing pursuit. Among the numerous oximes synthesized, in vitro reactivation is a standard approach in biological evaluation with little attention given to the pharmacokinetic properties of the compounds. This study reports a comprehensive physicochemical, pharmacokinetic, and safety profiling of five 3-hydroxy-2-pyridine aldoximes, which were recently shown to be potent AChE reactivators. The oxime JR595 was singled out as highly metabolically stable in human liver microsomes and non-cytotoxic oxime for SH-SY5Y neuroblastoma and 1321N1 astrocytoma cell lines and its pharmacokinetic profile was determined after intramuscular administration in mice. JR595 was rapidly absorbed into blood after 15 min with simultaneous distribution to the brain at up to about 40% of its blood concentration; however, it was eliminated both from the brain and blood within an hour. In addition, the MDCKII-MDR1 cell line assay showed that oxime JR595 was not a P-glycoprotein efflux pump substrate. Furthermore, preliminary antidotal study against multiple LD50 doses of VX and sarin in mice showed the potential of JR595 to provide desirable therapeutic outcomes with future improvements in its circulation time.
ESTHER : Zorbaz_2020_ACS.Chem.Neurosci__
PubMedSearch : Zorbaz_2020_ACS.Chem.Neurosci__
PubMedID: 32105443

Title : Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3 - Oukoloff_2019_Eur.J.Med.Chem_168_58
Author(s) : Oukoloff K , Coquelle N , Bartolini M , Naldi M , Le Guevel R , Bach S , Josselin B , Ruchaud S , Catto M , Pisani L , Denora N , Iacobazzi RM , Silman I , Sussman JL , Buron F , Colletier JP , Jean L , Routier S , Renard PY
Ref : Eur Journal of Medicinal Chemistry , 168 :58 , 2019
Abstract : Both cholinesterases (AChE and BChE) and kinases, such as GSK-3alpha/beta, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3alpha/beta (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5nM for human acetylcholinesterase (hAChE) and 7nM for GSK-3alpha/beta. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.
ESTHER : Oukoloff_2019_Eur.J.Med.Chem_168_58
PubMedSearch : Oukoloff_2019_Eur.J.Med.Chem_168_58
PubMedID: 30798053
Gene_locus related to this paper: torca-ACHE

Title : Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection - Pashirova_2018_J.Control.Release_290_102
Author(s) : Pashirova TN , Braiki A , Zueva IV , Petrov KA , Babaev VM , Burilova EA , Samarkina DA , Rizvanov IK , Souto EB , Jean L , Renard PY , Masson P , Zakharova LY , Sinyashin OG
Ref : J Control Release , 290 :102 , 2018
Abstract : A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160nm and negative zeta potential (-30 to -25mV) were stable for a period of 10months at 4 degrees C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8xLD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.
ESTHER : Pashirova_2018_J.Control.Release_290_102
PubMedSearch : Pashirova_2018_J.Control.Release_290_102
PubMedID: 30308259

Title : Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis - Galdeano_2018_Molecules_23_
Author(s) : Galdeano C , Coquelle N , Cieslikiewicz-Bouet M , Bartolini M , Perez B , Clos MV , Silman I , Jean L , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Molecules , 23 : , 2018
Abstract : Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.
ESTHER : Galdeano_2018_Molecules_23_
PubMedSearch : Galdeano_2018_Molecules_23_
PubMedID: 29534488
Gene_locus related to this paper: torca-ACHE

Title : Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents - Santoni_2018_J.Med.Chem_61_7630
Author(s) : Santoni G , de Sousa J , De la Mora E , Dias J , Jean L , Sussman JL , Silman I , Renard PY , Brown RCD , Weik M , Baati R , Nachon F
Ref : Journal of Medicinal Chemistry , 61 :7630 , 2018
Abstract : Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a nonquaternary oxime is also an undesired submicromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of the tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized and, in line with the prediction, displayed a 10-fold decrease in inhibition but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of new-generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication.
ESTHER : Santoni_2018_J.Med.Chem_61_7630
PubMedSearch : Santoni_2018_J.Med.Chem_61_7630
PubMedID: 30125110
Gene_locus related to this paper: torca-ACHE

Title : Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration - Zorbaz_2018_Chemistry_24_9675
Author(s) : Zorbaz T , Braiki A , Marakovic N , Renou J , De la Mora E , Macek Hrvat N , Katalinic M , Silman I , Sussman JL , Mercey G , Gomez C , Mougeot R , Perez B , Baati R , Nachon F , Weik M , Jean L , Kovarik Z , Renard PY
Ref : Chemistry , 24 :9675 , 2018
Abstract : A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential.
ESTHER : Zorbaz_2018_Chemistry_24_9675
PubMedSearch : Zorbaz_2018_Chemistry_24_9675
PubMedID: 29672968
Gene_locus related to this paper: torca-ACHE

Title : Probing the cholinergic system to understand neurodegenerative diseases -
Author(s) : Renard PY , Jean L
Ref : Future Med Chem , 9 :131 , 2017
PubMedID: 28097893

Title : On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM\/MM Approach - Driant_2017_Chembiochem_18_666
Author(s) : Driant T , Nachon F , Ollivier C , Renard PY , Derat E
Ref : Chembiochem , 18 :666 , 2017
Abstract : Acetylcholinesterase (AChE), an enzyme of the serine hydrolase superfamily, is a mediator of signal transmission at cholinergic synapses by catalyzing acetylcholine cleavage into acetate and choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds (like VX). Covalent inhibition of AChE does not revert spontaneously. Known reactivator compounds have limited action in restoring catalytic activity. QM/MM simulations of VX-inhibited AChE reactivation by pralidoxime (2-PAM), a classical reactivator, were performed. These afforded a broad view of the effect of protonation states of active-site residues, and provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM for both protonation states of Glu202 showed that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Because the active site of serine hydrolases is highly conserved, this work provides new insights on the interplay between the catalytic triad residues and this glutamate, newly identified as protonatable.
ESTHER : Driant_2017_Chembiochem_18_666
PubMedSearch : Driant_2017_Chembiochem_18_666
PubMedID: 28106328

Title : An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice - Calas_2017_Chem.Biol.Interact_267_11
Author(s) : Calas AG , Dias J , Rousseau C , Arboleas M , Touvrey-Loiodice M , Mercey G , Jean L , Renard PY , Nachon F
Ref : Chemico-Biological Interactions , 267 :11 , 2017
Abstract : Organophosphorus nerve agents, like VX, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). AChE inhibited by VX can be reactivated using powerful nucleophilic molecules, most commonly oximes, which are one major component of the emergency treatment in case of nerve agent intoxication. We present here a comparative in vivo study on Swiss mice of four reactivators: HI-6, pralidoxime and two uncharged derivatives of 3-hydroxy-2-pyridinaldoxime that should more easily cross the blood-brain barrier and display a significant central nervous system activity. The reactivability kinetic profile of the oximes is established following intraperitoneal injection in healthy mice, using an original and fast enzymatic method based on the reactivation potential of oxime-containing plasma samples. HI-6 displays the highest reactivation potential whatever the conditions, followed by pralidoxime and the two non quaternary reactivators at the dose of 50 mg/kg bw. But these three last reactivators display equivalent reactivation potential at the same dose of 100 mumol/kg bw. Maximal reactivation potential closely correlates to surviving test results of VX intoxicated mice.
ESTHER : Calas_2017_Chem.Biol.Interact_267_11
PubMedSearch : Calas_2017_Chem.Biol.Interact_267_11
PubMedID: 26972668

Title : A selective and sensitive near-infrared fluorescent probe for acetylcholinesterase imaging - Chao_2016_Chem.Commun.(Camb)_52_11599
Author(s) : Chao S , Krejci E , Bernard V , Leroy J , Jean L , Renard PY
Ref : Chem Commun (Camb) , 52 :11599 , 2016
Abstract : Two near infra-red (NIR) fluorescent probes HupNIR1 and HupNIR2 based on the huprine scaffold and cyanine 5.0 dye have been synthesised and evaluated in situ for the detection of acetylcholinesterases in different tissues. As anticipated by the initial properties of huprine, both probes displayed a high affinity and selectivity for AChE toward BChE, with IC50 values in the nanomolar range and without any non-specific binding in the tissues. HupNIR2 appears the best probe for AChE with a great selectivity and sensitivity for AChE even in the brain region displaying a low AChE concentration as striatum. Moreover, the binding of HupNIR2 is affected when AChE is inhibited with toxic molecules such as organophosphates. This work provides a new tool to visualize active AChE in biological applications.
ESTHER : Chao_2016_Chem.Commun.(Camb)_52_11599
PubMedSearch : Chao_2016_Chem.Commun.(Camb)_52_11599
PubMedID: 27604478

Title : Poster: Multi-target directed ligands: Electrophysiological characterization of an anticholinesterase inhibitor coupled to an agonist of alpha7 nicotinic acetylcholine receptor -
Author(s) : Araoz R , Bouet m , Bartolini M , Coquelle N , Colletier JP , Servent D , Molgo J , Jean L , Renard PY
Ref : Biochemical Pharmacology , 97 :621 , 2015

Title : Tryptoline-3-hydroxypyridinaldoxime conjugates as efficient reactivators of phosphylated human acetyl and butyrylcholinesterases - Renou_2014_Chem.Commun.(Camb)_50_3947
Author(s) : Renou J , Loiodice M , Arboleas M , Baati R , Jean L , Nachon F , Renard PY
Ref : Chem Commun (Camb) , 50 :3947 , 2014
Abstract : Two promising uncharged reactivators for inhibited human BChE and AChE have been described. These compounds show an ability to reactivate VX-inhibited BChE largely superior to those of known pyridinium aldoximes. Moreover, these oximes also exhibit a good ability to reactivate VX-, tabun- and paraoxon-inhibited human AChE.
ESTHER : Renou_2014_Chem.Commun.(Camb)_50_3947
PubMedSearch : Renou_2014_Chem.Commun.(Camb)_50_3947
PubMedID: 24599312

Title : Reaction site-driven regioselective synthesis of AChE inhibitors - Oueis_2014_Org.Biomol.Chem_12_156
Author(s) : Oueis E , Santoni G , Ronco C , Syzgantseva O , Tognetti V , Joubert L , Romieu A , Weik M , Jean L , Sabot C , Nachon F , Renard PY
Ref : Org Biomol Chem , 12 :156 , 2014
Abstract : The enzyme-directed synthesis is an emerging fragment-based lead discovery approach in which the biological target is able to assemble its own multidentate ligands from a pool of building blocks. Here, we report for the first time the use of the human acetylcholinesterase (AChE) as an enzyme for the design and synthesis of new potent heterodimeric huprine-based inhibitors. Both the specific click chemistry site within the protein and the regioselectivity of the Huisgen cycloaddition observed suggest promising alternatives in the design of efficient mono- and dimeric ligands of AChE. Finally, a detailed computational modelling of the click reaction was conducted to further understand the origin of this TGS selectivity.
ESTHER : Oueis_2014_Org.Biomol.Chem_12_156
PubMedSearch : Oueis_2014_Org.Biomol.Chem_12_156
PubMedID: 24216754

Title : First enzymatic hydrolysis\/thio-Michael addition cascade route to synthesis of AChE inhibitors - Oueis_2014_Chem.Commun.(Camb)_50_2043
Author(s) : Oueis E , Nachon F , Sabot C , Renard PY
Ref : Chem Commun (Camb) , 50 :2043 , 2014
Abstract : The irreversible Michael addition of thiols to acrylamides is reported as a new tool for the kinetic target-guided synthesis. In an unprecedented enzymatic hydrolysis/thio-Michael addition procedure, potent and selective acetylcholinesterase inhibitors are assembled by the enzyme using both its esterasic and templating ability.
ESTHER : Oueis_2014_Chem.Commun.(Camb)_50_2043
PubMedSearch : Oueis_2014_Chem.Commun.(Camb)_50_2043
PubMedID: 24418813

Title : Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase - Kliachyna_2014_Eur.J.Med.Chem_78C_455
Author(s) : Kliachyna M , Santoni G , Nussbaum V , Renou J , Sanson B , Colletier JP , Arboleas M , Loiodice M , Weik M , Jean L , Renard PY , Nachon F , Baati R
Ref : Eur Journal of Medicinal Chemistry , 78C :455 , 2014
Abstract : A series of new uncharged functional acetylcholinesterase (AChE) reactivators including heterodimers of tetrahydroacridine with 3-hydroxy-2-pyridine aldoximes and amidoximes has been synthesized. These novel molecules display in vitro reactivation potencies towards VX-, tabun- and paraoxon-inhibited human AChE that are superior to those of the mono- and bis-pyridinium aldoximes currently used against nerve agent and pesticide poisoning. Furthermore, these uncharged compounds exhibit a broader reactivity spectrum compared to currently approved remediation drugs.
ESTHER : Kliachyna_2014_Eur.J.Med.Chem_78C_455
PubMedSearch : Kliachyna_2014_Eur.J.Med.Chem_78C_455
PubMedID: 24704618

Title : Strategies for the selection of catalytic antibodies against organophosphorus nerve agents - Smirnov_2013_Chem.Biol.Interact_203_196
Author(s) : Smirnov IV , Belogurov AA, Jr. , Friboulet A , Masson P , Gabibov AG , Renard PY
Ref : Chemico-Biological Interactions , 203 :196 , 2013
Abstract : Among the strategies aimed at biocompatible means for organophosphorus nerve agents neutralization, immunoglobulins have attracted attention in the 1990's and 2000's both for their ability to immobilize the toxicants, but also for their ability to be turned into enzymatically active antibodies known as catalytic antibodies or abzymes (antibodies - enzymes). We will present here a critical review of the successive strategies used for the selection of these nerve agent-hydrolyzing abzymes, based on hapten design, namely antibodies raised against a wide variety of transition state analogs, and eventually the strategies based on anti-idiotypic antibodies and reactibodies.
ESTHER : Smirnov_2013_Chem.Biol.Interact_203_196
PubMedSearch : Smirnov_2013_Chem.Biol.Interact_203_196
PubMedID: 23123255

Title : Syntheses and in vitro evaluations of uncharged reactivators for human acetylcholinesterase inhibited by organophosphorus nerve agents - Renou_2013_Chem.Biol.Interact_203_81
Author(s) : Renou J , Mercey G , Verdelet T , Paunescu E , Gillon E , Arboleas M , Loiodice M , Kliachyna M , Baati R , Nachon F , Jean L , Renard PY
Ref : Chemico-Biological Interactions , 203 :81 , 2013
Abstract : Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant K(D) of inhibited enzyme-oxime complex, the reactivity rate constant kr and the second order reactivation rate constant k(r2) have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun-inhibited hAChE equivalent to those of 2-PAM.
ESTHER : Renou_2013_Chem.Biol.Interact_203_81
PubMedSearch : Renou_2013_Chem.Biol.Interact_203_81
PubMedID: 23111374

Title : Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase - Nachon_2013_Biochem.J_453_393
Author(s) : Nachon F , Carletti E , Ronco C , Trovaslet M , Nicolet Y , Jean L , Renard PY
Ref : Biochemical Journal , 453 :393 , 2013
Abstract : The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, pi-pi/cation-pi interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.
ESTHER : Nachon_2013_Biochem.J_453_393
PubMedSearch : Nachon_2013_Biochem.J_453_393
PubMedID: 23679855
Gene_locus related to this paper: human-ACHE , human-BCHE

Title : Phenyltetrahydroisoquinoline-pyridinaldoxime conjugates as efficient uncharged reactivators for the dephosphylation of inhibited human acetylcholinesterase - Mercey_2012_J.Med.Chem_55_10791
Author(s) : Mercey G , Renou J , Verdelet T , Kliachyna M , Baati R , Gillon E , Arboleas M , Loiodice M , Nachon F , Jean L , Renard PY
Ref : Journal of Medicinal Chemistry , 55 :10791 , 2012
Abstract : Pyridinium and bis-pyridinium aldoximes are used as antidotes to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus nerve agents. Herein, we described a series of nine nonquaternary phenyltetrahydroisoquinoline-pyridinaldoxime conjugates more efficient than or as efficient as pyridinium oximes to reactivate VX-, tabun- and ethyl paraoxon-inhibited human AChE. This study explores the structure-activity relationships of this new family of reactivators and shows that 1b-d are uncharged hAChE reactivators with a broad spectrum.
ESTHER : Mercey_2012_J.Med.Chem_55_10791
PubMedSearch : Mercey_2012_J.Med.Chem_55_10791
PubMedID: 23148598

Title : Huprine derivatives as sub-nanomolar human acetylcholinesterase inhibitors: from rational design to validation by X-ray crystallography - Ronco_2012_ChemMedChem_7_400
Author(s) : Ronco C , Carletti E , Colletier JP , Weik M , Nachon F , Jean L , Renard PY
Ref : ChemMedChem , 7 :400 , 2012
Abstract : This complete study - from rational design to validation by X-ray crystallography allowed us to discover two sub-nanomolar hAChE inhibitors (430 and 530 pM) grafted with an easily derivatized linker directed toward the AChE peripheral site. The crystal structure of mouse AChE in complex with compound 4 was solved and confirms the favorable position of the triazole in the active site gorge, paving the way for a new class of bifunctional ligands.
ESTHER : Ronco_2012_ChemMedChem_7_400
PubMedSearch : Ronco_2012_ChemMedChem_7_400
PubMedID: 22052791
Gene_locus related to this paper: mouse-ACHE

Title : Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents - Mercey_2012_Acc.Chem.Res_45_756
Author(s) : Mercey G , Verdelet T , Renou J , Kliachyna M , Baati R , Nachon F , Jean L , Renard PY
Ref : Acc Chem Res , 45 :756 , 2012
Abstract : Since the September 11, 2001, terrorist attacks in the United States, the specter of a chemical threat against civilian populations has renewed research interest in chemical warfare agents, their mechanisms of action, and treatments that reverse their effects. In this Account, we focus specifically on organophosphorus nerve agents (OPNAs). Although some OPNAs are used as pest control, the most toxic chemicals in this class are used as chemical warfare agents in armed conflicts. The acute toxicity of OPNAs results from the irreversible inhibition of acetylcholinesterase (AChE, EC via the formation of a covalent P-O bond at the serine hydroxyl group in the enzyme active site. AChE breaks down the neurotransmitter acetylcholine at neuronal synapses and neuromuscular junctions. The irreversible inhibition of AChE causes the neurotransmitter to accumulate in the synaptic cleft, leading to overstimulation of cholinergic receptors, seizures, respiratory arrest, and death. The current treatment for OPNA poisoning combines an antimuscarinic drug (e.g., atropine), an anticonvulsant drug (e.g., diazepam), and an AChE reactivator of the pyridinium aldoxime family (pralidoxime, trimedoxime, obidoxime, HI-6, HLo-7). Because of their high nucleophilicity, oximes can displace the phosphyl group from the catalytic serine, thus restoring the enzyme's catalytic activity. During 50 years of research in the reactivator field, researchers have synthesized and tested numerous structural modifications of monopyridinium oximes and bispyridinium oximes. In the past decade, medicinal chemists have focused their research on the more efficient bispyridinium reactivators, but all known reactivators have several drawbacks. First, due to their permanent positive charge, they do not cross the blood-brain barrier (BBB) efficiently and do not readily reactivate AChE in the central nervous system. Second, no single oxime is efficient against a wide variety of OPNAs. Third, oximes cannot reactivate "aged" AChE. This Account summarizes recent strategies for the development of AChE reactivators capable of crossing the BBB. The use of nanoparticulate transport and inhibition of P-glycoprotein efflux pumps improves BBB transport of these AChE reactivators. Chemical modifications that increased the lipophilicity of the pyridinium aldoximes, the addition of a fluorine atom and the replacement of a pyridyl ring with a dihydropyridyl moiety, enhances BBB permeability. The glycosylation of pyridine aldoximes facilitates increased BBB penetration via the GLUT-1 transport system. The development of novel uncharged reactivators that can move efficiently across the BBB represents one of the most promising of these new strategies.
ESTHER : Mercey_2012_Acc.Chem.Res_45_756
PubMedSearch : Mercey_2012_Acc.Chem.Res_45_756
PubMedID: 22360473

Title : Screening of new huprines--inhibitors of acetylcholinesterases by electrospray ionization ion trap mass spectrometry - Ziemianin_2012_J.Pharm.Biomed.Anal_70_1
Author(s) : Ziemianin A , Ronco C , Dole R , Jean L , Renard PY , Lange CM
Ref : J Pharm Biomed Anal , 70 :1 , 2012
Abstract : Acetylcholinesterase inhibitors (AChEI) are one of the drugs families validated for clinical use in the treatment of Alzheimer's disease (AD). For this reason, finding new more potent and more selective AChEIs is always of interest. Since 1961, the inhibitory activity of AChEI is evaluated through the Ellman's method. Herein, we reported a MS-based evaluation of potential new AChEI with the determination of their inhibitory activity (IC(50) and K(I)). Compared to the Ellman's method, that uses the substrate analog acetylthiocholine, the electrospray ionization ion trap mass spectrometry (ESI-IT-MS) consists in monitoring the conversion ratio of a low concentration of the natural substrate - acetylcholine to choline. We present here the inhibition activity of huprine X and six of its derivates (bearing different functional groups at position 9) towards the recombinant human (rhAChE) and Electrophorus electricus acetylcholinesterase (EelAChE). Mechanisms of action of selected inhibitors were evaluated by means of Lineweaver-Burk plot analysis. The Michaelis-Menten constants (K(M)), inhibitory constants (K(I)) were examined as well as the IC(50) to allow classifying a series of huprine derivatives by inhibition potency by a comparison with a reference (huprine X). Our results demonstrate that these drugs are very potent AChE inhibitors, especially (+/-)-huprine 6 with an inhibitory activity on recombinant human AChE (rhAChE) in the picomolar range. This study reveals the interest of huprine compounds in the treatment of AD.
ESTHER : Ziemianin_2012_J.Pharm.Biomed.Anal_70_1
PubMedSearch : Ziemianin_2012_J.Pharm.Biomed.Anal_70_1
PubMedID: 22677656

Title : Human butyrylcholinesterase produced in insect cells: huprine-based affinity purification and crystal structure - Brazzolotto_2012_Febs.J_279_2905
Author(s) : Brazzolotto X , Wandhammer M , Ronco C , Trovaslet M , Jean L , Lockridge O , Renard PY , Nachon F
Ref : Febs J , 279 :2905 , 2012
Abstract : Butyrylcholinesterase is a serine hydrolase present in all mammalian tissues. It can accommodate larger substrates or inhibitors than acetylcholinesterase, the enzyme responsible for hydrolysis of the neurotransmitter acetylcholine in the central nervous system and neuromuscular junctions. AChE is the specific target of organophosphorous pesticides and warfare nerve agents, while BChE is their stoichiometric bioscavenger. Conversion of BChE into a catalytic bioscavenger by rational design or designing reactivators specific to BChE required structural data obtained with a recombinant low-glycosylated human BChE expressed in Chinese hamster ovary cells. This expression system yields about 1 mg of pure enzyme per liter of cell culture. Here, we report an improved expression system with 4-fold higher yield for truncated human BChE with all glycosylation sites present using insect cells. We developed a fast purification protocol of the recombinant protein using a huprine-based affinity chromatography superior to the classical procainamide-based affinity. The purified BChE crystallized in different conditions and space group than those for the recombinant low-glycosylated protein produced in Chinese hamster ovary cells. The crystals diffracted to 2.5 A. The overall monomer structure is similar to the low-glycosylated structure but for the presence of the additional glycans. Remarkably, the carboxylic acid molecule systematically bound to the catalytic serine in the low-glycosylated structure is also present in this new structure, despite the different expression system, purification protocol and crystallization conditions.
ESTHER : Brazzolotto_2012_Febs.J_279_2905
PubMedSearch : Brazzolotto_2012_Febs.J_279_2905
PubMedID: 22726956
Gene_locus related to this paper: human-BCHE

Title : First efficient uncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase - Mercey_2011_Chem.Commun.(Camb)_47_5295
Author(s) : Mercey G , Verdelet T , Saint-Andre G , Gillon E , Wagner A , Baati R , Jean L , Nachon F , Renard PY
Ref : Chem Commun (Camb) , 47 :5295 , 2011
Abstract : Nerve agents are highly toxic organophosphorus compounds with strong inhibition potency against acetylcholinesterase (AChE). Herein, we describe two first extremely promising uncharged reactivators for poisoned human AChE with a superior or similar in vitro ability to reactivate the enzyme as compared to that of HI-6, obidoxime, TMB-4 and HLo-7.
ESTHER : Mercey_2011_Chem.Commun.(Camb)_47_5295
PubMedSearch : Mercey_2011_Chem.Commun.(Camb)_47_5295
PubMedID: 21451868

Title : Optimized strategies to synthesize beta-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers - Le Provost_2011_Org.Biomol.Chem_9_3026
Author(s) : Le Provost R , Wille T , Louise L , Masurier N , Muller S , Reiter G , Renard PY , Lafont O , Worek F , Estour F
Ref : Org Biomol Chem , 9 :3026 , 2011
Abstract : A new generation of organophosphate (OP) scavengers was obtained by synthesis of beta-cyclodextrin-oxime derivatives 8-12. Selective monosubstitution of beta-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the oligosaccharide was closely related to the nature of the incoming group. For this purpose, non-conventional activation conditions were also evaluated. Intermediates 5 and 7 were then obtained with the better yields under ultrasounds irradiation. Finally, the desired compounds 8-10 were obtained from 5-7 in high purity by desilylation using potassium fluoride. Quaternarisation of compounds 8 and 9 was carried out. OP hydrolytic activity of compounds 8-12 was evaluated against cyclosarin (GF) and VX. None of the tested compounds was active against VX, but these five cyclodextrin derivatives detoxified GF, and the most active scavengers 10 and 11 allowed an almost complete hydrolysis of GF within 10 min. Even more fascinating is the fact that compounds 9 and 10 were able to hydrolyze enantioselectively GF.
ESTHER : Le Provost_2011_Org.Biomol.Chem_9_3026
PubMedSearch : Le Provost_2011_Org.Biomol.Chem_9_3026
PubMedID: 21373706

Title : New huprine derivatives functionalized at position 9 as highly potent acetylcholinesterase inhibitors - Ronco_2011_ChemMedChem_6_876
Author(s) : Ronco C , Foucault R , Gillon E , Bohn P , Nachon F , Jean L , Renard PY
Ref : ChemMedChem , 6 :876 , 2011
Abstract : A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues (1, 2, 6-9, 13-15, and 23) are active in the low nanomolar range (IC(50) <5 nM), very close to the parent compound huprine X. Compounds 2, 6, and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700-1160-fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl-binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines (2, 6, and 7) showed that most of the difference in K(D) is accounted by a decrease in k(on) , which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC(50) =1.1 nM) and showed a rather weak toxicity (LD(50) =40 mg kg(-1) ) and an ability to cross the blood-brain barrier with doses above 15 mg kg(-1).
ESTHER : Ronco_2011_ChemMedChem_6_876
PubMedSearch : Ronco_2011_ChemMedChem_6_876
PubMedID: 21344648

Title : A HTS assay for the detection of organophosphorus nerve agent scavengers - Louise-Leriche_2010_Chemistry_16_3510
Author(s) : Louise-Leriche L , Paunescu E , Saint-Andre G , Baati R , Romieu A , Wagner A , Renard PY
Ref : Chemistry , 16 :3510 , 2010
Abstract : A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.
ESTHER : Louise-Leriche_2010_Chemistry_16_3510
PubMedSearch : Louise-Leriche_2010_Chemistry_16_3510
PubMedID: 20143367

Title : Synthesis and structure-activity relationship of Huprine derivatives as human acetylcholinesterase inhibitors - Ronco_2009_Bioorg.Med.Chem_17_4523
Author(s) : Ronco C , Sorin G , Nachon F , Foucault R , Jean L , Romieu A , Renard PY
Ref : Bioorganic & Medicinal Chemistry , 17 :4523 , 2009
Abstract : New series of Huprine (12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolines) derivatives have been synthesized and their inhibiting activities toward recombinant human acetylcholinesterase (rh-AChE) are reported. We have synthesized two series of Huprine analogues; in the first one, the benzene ring of the quinoline moiety has been replaced by different heterocycles or electron-withdrawing or electron-donating substituted phenyl group. The second one has been designed in order to evaluate the influence of modification at position 12 where different short linkers have been introduced on the Huprine X, Y skeletons. All these molecules have been prepared from ethyl- or methyl-bicyclo[3.3.1]non-6-en-3-one via Friedlander reaction involving selected o-aminocyano aromatic compounds. The synthesis of two heterodimers based on these Huprines has been also reported. Activities from moderate to same range than the most active Huprines X and Y taken as references have been obtained, the most potent analogue being about three times less active than parent Huprines X and Y. Topologic data have been inferred from molecular dockings and variations of activity between the different linkers suggest future structural modifications for activity improvement.
ESTHER : Ronco_2009_Bioorg.Med.Chem_17_4523
PubMedSearch : Ronco_2009_Bioorg.Med.Chem_17_4523
PubMedID: 19473849

Title : Easy access to phosphonothioates - Renard_2002_Chemistry_8_2910
Author(s) : Renard PY , Schwebel H , Vayron P , Josien L , Valleix A , Mioskowski C
Ref : Chemistry , 8 :2910 , 2002
Abstract : A new and particularly mild method for the formation of phosphorus-sulfur bonds has been achieved through base-catalyzed addition of thiocyanate to the corresponding H-phosphine oxide, phosphinate, or phosphonate. This reaction procedure offers many advantages: the use as starting material of a stable and not oxygen-sensitive phosphorus(v) species, particularly mild and nonaqueous reaction conditions and workup (a pivotal point for these sensitive phosphonothioates), and, through optimized access to thiocyanates, a wider scope of substrates. This method has been applied to achieve the synthesis of substrate analogues for the study of antibody-catalyzed hydrolysis of acetylcholinesterase inhibitor PhX (11).
ESTHER : Renard_2002_Chemistry_8_2910
PubMedSearch : Renard_2002_Chemistry_8_2910
PubMedID: 12489219

Title : Design and synthesis of chemiluminescent probes for the detection of cholinesterase activity - Sabelle_2002_J.Am.Chem.Soc_124_4874
Author(s) : Sabelle S , Renard PY , Pecorella K , de Suzzoni-Dezard S , Creminon C , Grassi J , Mioskowski C
Ref : Journal of the American Chemical Society , 124 :4874 , 2002
Abstract : Acetylcholinesterase is one of the most widely used and studied enzymes. Not only does this enzyme regulate neurotransmission (and thus play a key role in neurodegenerative processes) but it is also a prime target for pest control agents and warfare agents. Above all, due to its particularly high turnover rate, acetylcholinesterase is among the most efficient reporter enzymes yet described (for use as enzymatic tracer in immunoassays, for instance). However, its activity is detected through a colorimetric reagent, the Ellman reagent, which displays low detection limits and is often subject to background perturbations. In the course of our search for a more sensitive detection assay, we describe here a first-generation 1,2-dioxetane chemiluminescent probe, based on chemically induced electron exchange luminescence, which has an approximately 10 times lower detection limit than the Ellman colorimetric assay (2.5 x 10(-19) mol for Electrophorus electricus AChE in its tetrameric form).
ESTHER : Sabelle_2002_J.Am.Chem.Soc_124_4874
PubMedSearch : Sabelle_2002_J.Am.Chem.Soc_124_4874
PubMedID: 11971738

Title : Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands - Anastassiadou_2001_Bioorg.Med.Chem_9_585
Author(s) : Anastassiadou M , Danoun S , Crane L , Baziard-Mouysset G , Payard M , Caignard DH , Rettori MC , Renard PY
Ref : Bioorganic & Medicinal Chemistry , 9 :585 , 2001
Abstract : Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I1 and I2) and alpha-adrenergic (alpha1 and alpha2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha-adrenergic affinity. I1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2'-methoxyphenyl)-imidazoline (17) is one of the best I1 ligands ever reported (pKi = 8.53 and I1/I2 > 3388). On the other hand, I2 selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3'-fluoro-4'-tolyl)-imidazoline (31) is a new potent ligand for the I2 sites with high selectivity (pKi = 8.53 and I2/I1 > 3388).
ESTHER : Anastassiadou_2001_Bioorg.Med.Chem_9_585
PubMedSearch : Anastassiadou_2001_Bioorg.Med.Chem_9_585
PubMedID: 11310592

Title : Toward antibody-catalyzed hydrolysis of organophosphorus poisons - Vayron_2000_Proc.Natl.Acad.Sci.U.S.A_97_7058
Author(s) : Vayron P , Renard PY , Taran F , Creminon C , Frobert Y , Grassi J , Mioskowski C
Ref : Proc Natl Acad Sci U S A , 97 :7058 , 2000
Abstract : We report here our preliminary results on the use of catalytic antibodies as an approach to neutralizing organophosphorus chemical weapons. A first-generation hapten, methyl-alpha-hydroxyphosphinate Ha, was designed to mimic the approach of an incoming water molecule for the hydrolysis of exceedingly toxic methylphosphonothioate VX (1a). A moderate protective activity was first observed on polyclonal antibodies raised against Ha. The results were further confirmed by using a mAb PAR 15 raised against phenyl-alpha-hydroxyphosphinate Hb, which catalyzes the hydrolysis of PhX (1b), a less toxic phenylphosphonothioate analog of VX with a rate constant of 0.36 M(-1) x min(-1) at pH 7.4 and 25 degrees C, which corresponds to a catalytic proficiency of 14,400 M(-1) toward the rate constant for the uncatalyzed hydrolysis of 1b. This is a demonstration on the organophosphorus poisons themselves that mAbs can catalytically hydrolyze nerve agents, and a significant step toward the production of therapeutically active abzymes to treat poisoning by warfare agents.
ESTHER : Vayron_2000_Proc.Natl.Acad.Sci.U.S.A_97_7058
PubMedSearch : Vayron_2000_Proc.Natl.Acad.Sci.U.S.A_97_7058
PubMedID: 10860971