Dias J


Full name : Dias Jose

First name : Jose

Mail : French Armed Forces Biomedical Research Institute, Toxicology and chemical risks department, Bretigny-sur-Orge

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Country : France

Email : jose.dias@irba.fr

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References (16)

Title : Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases - Kolic_2024_Biomolecules_14_588
Author(s) : Kolic D , Sinko G , Jean L , Chioua M , Dias J , Marco-Contelles J , Kovarik, Z
Ref : Biomolecules , 14 :588 , 2024
Abstract : Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the bloodbrain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 1030% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
ESTHER : Kolic_2024_Biomolecules_14_588
PubMedSearch : Kolic_2024_Biomolecules_14_588

Title : The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives - Voros_2024_Chem.Biol.Interact__110973
Author(s) : Voros C , Dias J , Timperley CM , Nachon F , Brown RCD , Baati R
Ref : Chemico-Biological Interactions , :110973 , 2024
Abstract : The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.
ESTHER : Voros_2024_Chem.Biol.Interact__110973
PubMedSearch : Voros_2024_Chem.Biol.Interact__110973
PubMedID: 38574837

Title : Inhibition of Human Cholinesterases and In Vitro beta-Amyloid Aggregation by Rationally Designed Peptides - Sanchis_2023_ChemMedChem__e202200691
Author(s) : Sanchis I , Spinelli R , Dias J , Brazzolotto X , Rietmann A , Aimaretti F , Siano AS
Ref : ChemMedChem , :e202200691 , 2023
Abstract : The multifactorial nature of Alzheimer's disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD-associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE-induced β-amyloid peptide (Aβ) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL-NH(2)) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC(50)value against hAChE reported for a peptide (0.99 +/- 0.02 micro M) and inhibited 94.2% +/- 1.2 of AChE-induced Aβ aggregation at 10 micro M. Furthermore, it inhibited hBChE (IC(50), 15.44 +/- 0.91 micro M), showed no 'in vivo' toxicity in brine shrimp and had shown moderated radical scavenging and Fe(2+) chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors.
ESTHER : Sanchis_2023_ChemMedChem__e202200691
PubMedSearch : Sanchis_2023_ChemMedChem__e202200691
PubMedID: 36995341

Title : Grid-type Quaternary Metallosupramolecular Compounds Inhibit Human Cholinesterases through Dynamic Multivalent Interactions - Nachon_2022_Chembiochem_23_e202200456
Author(s) : Nachon F , Brazzolotto X , Dias J , Courageux C , Drozdz W , Cao XY , Stefankiewicz AR , Lehn JM
Ref : Chembiochem , 23 :e202200456 , 2022
Abstract : We report herein the implementation of coordination complexes containing two types of cationic moieties, i.e. pyridinium and ammonium quaternary salt, as potential inhibitors of human cholinesterase enzymes. Utilization of ligands containing NNO-coordination site and binding zinc metal ion allowed obtaining mono- and tetra-nuclear complexes with corner and grid structural type respectively, thus affecting the overall charge of the compounds (from +1 to +8). It enabled for the first time to examine the multivalency effect of metallosupramolecular species on their inhibitory abilities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Importantly, resolution of the crystal structures of the obtained enzyme-substrate complexes provided a better understanding of the inhibition process at the molecular level.
ESTHER : Nachon_2022_Chembiochem_23_e202200456
PubMedSearch : Nachon_2022_Chembiochem_23_e202200456
PubMedID: 36193860
Gene_locus related to this paper: human-BCHE

Title : From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series - Meden_2022_Eur.J.Med.Chem_230_114248
Author(s) : Meden A , Knez D , Brazzolotto X , Nachon F , Dias J , Svete J , Stojan J , Groselj U , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 230 :114248 , 2022
Abstract : Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold) (Chierrito et al., 2018).. Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the neccessary structural infromation for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.
ESTHER : Meden_2022_Eur.J.Med.Chem_230_114248
PubMedSearch : Meden_2022_Eur.J.Med.Chem_230_114248
PubMedID: 35299116
Gene_locus related to this paper: human-BCHE

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 drug-like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database - Miles_2021_Chem.Biol.Drug.Des__
Author(s) : Miles JA , Ng JH , Sreenivas BY , Courageux C , Igert A , Dias J , McGeary RP , Brazzolotto X , Ross BP
Ref : Chemical Biology Drug Des , : , 2021
Abstract : Cholinesterase inhibitors remain the mainstay of Alzheimer's disease treatment, and the search for new inhibitors with better efficacy and side effect profiles is ongoing. Virtual screening (VS) is a powerful technique for searching large compound databases for potential hits. This study used a sequential VS workflow combining ligand-based VS, molecular docking and physicochemical filtering to screen for CNS drug-like acetylcholinesterase inhibitors (AChEIs) amongst the 6.9 million compounds of the CoCoCo database. Eleven in silico hits were initially selected, resulting in the discovery of an AChEI with a K(i) of 3.2 microM. In vitro kinetics and in silico molecular dynamics experiments informed the selection of an additional seven analogues. This led to the discovery of two further AChEIs, with K(i) values of 2.9 microM and 0.65 microM. All three compounds exhibited reversible, mixed inhibition of AChE. Importantly, the in silico physicochemical filter facilitated the discovery of CNS drug-like compounds, such that all three inhibitors displayed high in vitro blood-brain barrier model permeability.
ESTHER : Miles_2021_Chem.Biol.Drug.Des__
PubMedSearch : Miles_2021_Chem.Biol.Drug.Des__
PubMedID: 33455074

Title : Development of versatile and potent monoquaternary reactivators of acetylcholinesterase - Gorecki_2021_Arch.Toxicol__
Author(s) : Gorecki L , Hepnarova V , Karasova JZ , Hrabinova M , Courageux C , Dias J , Kucera T , Kobrlova T , Muckova L , Prchal L , Malinak D , Jun D , Musilek K , Worek F , Nachon F , Soukup O , Korabecny J
Ref : Archives of Toxicology , : , 2021
Abstract : To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
ESTHER : Gorecki_2021_Arch.Toxicol__
PubMedSearch : Gorecki_2021_Arch.Toxicol__
PubMedID: 33517499

Title : Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases - Chavarria_2021_Antioxidants.(Basel)_10_329
Author(s) : Chavarria D , Da Silva O , Benfeito S , Barreiro S , Garrido J , Cagide F , Soares P , Remiao F , Brazzolotto X , Nachon F , Oliveira PJ , Dias J , Borges F
Ref : Antioxidants (Basel) , 10 :329 , 2021
Abstract : Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the Pi-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP(+)) conjugates (compounds 2-5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC(50) values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2-5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2-5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2-5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.
ESTHER : Chavarria_2021_Antioxidants.(Basel)_10_329
PubMedSearch : Chavarria_2021_Antioxidants.(Basel)_10_329
PubMedID: 33672269
Gene_locus related to this paper: human-ACHE , human-BCHE

Title : Discovery of multifunctional anti-Alzheimers agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters - Pasieka_2021_Eur.J.Med.Chem_218_113397
Author(s) : Pasieka A , Panek D , Jonczyk J , Godyn J , Szalaj N , Latacz G , Tabor J , Mezeiova E , Chantegreil F , Dias J , Knez D , Lu J , Pi R , Korabecny J , Brazzolotto X , Gobec S , Hofner G , Wanner K , Wieckowska Q , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 218 :113397 , 2021
Abstract : Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (Abeta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 microM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 microM; inhibition of Abeta aggregation = 57.9% at 10 microM; mGAT1 IC50 = 10.96 microM; and mGAT2 IC50 = 19.05 microM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 microM and IC50 = 2.95 microM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.
ESTHER : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedSearch : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedID: 33838585

Title : Chemoselective Hydrogenation of 6-Alkynyl-3-fluoro-2-pyridinaldoximes: Access to First-in-Class 6-Alkyl-3-Fluoro-2-pyridinaldoxime Scaffolds as New Reactivators of Sarin-Inhibited Human Acetylcholinesterase with Increased Blood-Brain Barrier Permeability - Yerri_2020_Chemistry_26_15035
Author(s) : Yerri J , Dias J , Nimmakayala MR , Razafindrainibe F , Courageux C , Gastellier AJ , Jegoux J , Coisne C , Landry C , Gosselet F , Hachani J , Goossens JF , Dehouck MP , Nachon F , Baati R
Ref : Chemistry , 26 :15035 , 2020
Abstract : Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.
ESTHER : Yerri_2020_Chemistry_26_15035
PubMedSearch : Yerri_2020_Chemistry_26_15035
PubMedID: 32633095

Title : Rapid discovery of a selective butyrylcholinesterase inhibitor using structure-based virtual screening - Miles_2020_Bioorg.Med.Chem.Lett__127609
Author(s) : Miles JA , Kapure JS , Singh Deora G , Courageux C , Igert A , Dias J , McGeary RP , Brazzolotto X , Ross BP
Ref : Bioorganic & Medicinal Chemistry Lett , :127609 , 2020
Abstract : Acetylcholinesterase inhibitors are the mainstay of Alzheimer's disease treatments, despite only short-term symptomatic benefits and severe side effects. Selective butyrylcholinesterase inhibitors (BuChEIs) may be more effective treatments in late-stage Alzheimer's disease with fewer side effects. Virtual screening is a powerful tool for identifying potential inhibitors in large digital compound databases. This study used structure-based virtual screening combined with physicochemical filtering to screen two the InterBioScreen and Maybridge databases for novel selective BuChEIs. The workflow rapidly identified 22 potential hits in silico, resulting in the discovery of a human BuChEI with low-micromolar potency in vitro (IC(50) 2.4 muM) and high selectivity for butyrylcholinesterase over acetylcholinesterase. The compound was a rapidly reversible BuChEI with mixed-model in vitro inhibition kinetics. The binding interactions were investigated using in silico molecular dynamics, and by developing structure-activity relationships using nine analogues. The compound also displayed high permeability in an in vitro model of the blood-brain barrier.
ESTHER : Miles_2020_Bioorg.Med.Chem.Lett__127609
PubMedSearch : Miles_2020_Bioorg.Med.Chem.Lett__127609
PubMedID: 33039562

Title : Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime - Calas_2020_Biomolecules_10_
Author(s) : Calas AG , Hanak AS , Jaffre N , Nervo A , Dias J , Rousseau C , Courageux C , Brazzolotto X , Villa P , Obrecht A , Goossens JF , Landry C , Hachani J , Gosselet F , Dehouck MP , Yerri J , Kliachyna M , Baati R , Nachon F
Ref : Biomolecules , 10 : , 2020
Abstract : (1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood-brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.
ESTHER : Calas_2020_Biomolecules_10_
PubMedSearch : Calas_2020_Biomolecules_10_
PubMedID: 32512884

Title : New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease - Zueva_2019_Neuropharmacol_155_131
Author(s) : Zueva IV , Dias J , Lushchekina SV , Semenov VE , Mukhamedyarov MA , Pashirova TN , Babaev VM , Nachon F , Petrova N , Nurullin LF , Zakharova LY , Ilyin VI , Masson P , Petrov KA
Ref : Neuropharmacology , 155 :131 , 2019
Abstract : Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5mg/kg, i.p) and donepezil (0.75mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action.
ESTHER : Zueva_2019_Neuropharmacol_155_131
PubMedSearch : Zueva_2019_Neuropharmacol_155_131
PubMedID: 31132435
Gene_locus related to this paper: human-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 : 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