Loiodice M

References (10)

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 : 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 : A step toward the reactivation of aged cholinesterases - Crystal structure of ligands binding to aged human butyrylcholinesterase - Wandhammer_2013_Chem.Biol.Interact_203_19
Author(s) : Wandhammer M , De Koning MC , van Grol M , Loiodice M , Saurel L , Noort D , Goeldner M , Nachon F
Ref : Chemico-Biological Interactions , 203 :19 , 2013
Abstract : Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase.
ESTHER : Wandhammer_2013_Chem.Biol.Interact_203_19
PubMedSearch : Wandhammer_2013_Chem.Biol.Interact_203_19
PubMedID: 22922115
Gene_locus related to this paper: human-BCHE

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 : 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 : Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents - Trovaslet-Leroy_2011_Toxicol.Lett_206_14
Author(s) : Trovaslet-Leroy M , Musilova L , Renault F , Brazzolotto X , Misik J , Novotny L , Froment MT , Gillon E , Loiodice M , Verdier L , Masson P , Rochu D , Jun D , Nachon F
Ref : Toxicol Lett , 206 :14 , 2011
Abstract : Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120-fold. Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Thus, we stress that interest for hPON1 must not fade away, and in particular, the 3D structure of the hPON1 eventually in complex with OP has to be solved.
ESTHER : Trovaslet-Leroy_2011_Toxicol.Lett_206_14
PubMedSearch : Trovaslet-Leroy_2011_Toxicol.Lett_206_14
PubMedID: 21683774

Title : Preparation and characterization of methoxy polyethylene glycol-conjugated phosphotriesterase as a potential catalytic bioscavenger against organophosphate poisoning - Jun_2010_Chem.Biol.Interact_187_380
Author(s) : Jun D , Musilova L , Link M , Loiodice M , Nachon F , Rochu D , Renault F , Masson P
Ref : Chemico-Biological Interactions , 187 :380 , 2010
Abstract : Bioscavengers are considered as promising antidotes against organophosphate poisoning. We focused on a bacterial phosphotriesterase (PTE) expressed in Escherichia coli. The main disadvantage of this non-human catalytic bioscavenger is its relatively short half-life in the organism and strong immunogenicity after repeated administration. Therefore, we prepared different methoxy polyethylene glycol (MPEG)-conjugated recombinant PTE as a potential catalytic bioscavenger with the aim to improve its biological properties. Enzyme was modified with two linear monofunctional MPEG derivatives with reactive aldehyde group of molecular weight 2 kDa and 5 kDa. We optimized reaction conditions (reagent ratios, temperature and duration of modification reaction) and we prepared homogeneous population of fully modified recombinant PTE with molecular weight around 52 kDa and 76 kDa, respectively. Modified PTE was characterized using SDS-PAGE and MALDI-TOF and by determining K(m) and V(max). We also investigated thermal stability of modified enzyme at 37 degrees C. Based on our results, for future in vivo evaluation of pharmacokinetics and pharmacodynamics properties, we selected recombinant PTE modified with 5 kDa MPEG aldehyde for its superior thermal stability.
ESTHER : Jun_2010_Chem.Biol.Interact_187_380
PubMedSearch : Jun_2010_Chem.Biol.Interact_187_380
PubMedID: 20230809

Title : Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun. - Carletti_2009_Biochem.J_421_97
Author(s) : Carletti E , Aurbek N , Gillon E , Loiodice M , Nicolet Y , Fontecilla-Camps JC , Masson P , Thiermann H , Nachon F , Worek F
Ref : Biochemical Journal , 421 :97 , 2009
Abstract : hBChE [human BChE (butyrylcholinesterase)] naturally scavenges OPs (organophosphates). This bioscavenger is currently in Clinical Phase I for pretreatment of OP intoxication. Phosphylated ChEs (cholinesterases) can undergo a spontaneous time-dependent process called 'aging' during which the conjugate is dealkylated, leading to creation of an enzyme that cannot be reactivated. hBChE inhibited by phosphoramidates such as tabun displays a peculiar resistance to oxime-mediated reactivation. We investigated the basis of oxime resistance of phosphoramidyl-BChE conjugates by determining the kinetics of inhibition, reactivation (obidoxime {1,1'-(oxybis-methylene) bis[4-(hydroxyimino) methyl] pyridinium dichloride}, TMB-4(Trimedoxime) [1,3-trimethylene-bis(4-hydroxyiminomethylpyridinium) dibromide], HL 7 {1-[[[4-(aminocarbonyl) pyridinio]methoxy]methyl]-2,4-bis-[(hydroxyimino)methyl] pyridinium dimethanesulfonate)}, HI-6 {1-[[[4-(aminocarbonyl) pyridinio] methoxy] methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride monohydrate} and aging, and the crystal structures of hBChE inhibited by different N-monoalkyl and N,N-dialkyl tabun analogues. The refined structures of aged hBChE conjugates show that aging proceeds through O-dealkylation of the P(R) enantiomer of N,N-diethyl and N-propyl analogues, with subsequent formation of a salt bridge preventing reactivation, similarly to a previous observation made on tabun-ChE conjugates. Interestingly, the N-methyl analogue projects its amino group towards the choline-binding pocket, so that aging proceeds through deamination. This orientation results from a preference of hBChE's acyl-binding pocket for larger than 2-atoms linear substituents. The correlation between the inhibitory potency and the N-monoalkyl chain length is related to increasingly optimized interactions with the acyl-binding pocket as shown by the X-ray structures. These kinetics and X-ray data lead to a structure-activity relationship that highlights steric and electronic effects of the amino substituent of phosphoramidate. This study provides the structural basis to design new oximes capable of reactivating phosphoramidyl-hBChE conjugates after intoxication, notably when hBChE is used as pretreatment, or to design BChE-based catalytic bioscavengers.
ESTHER : Carletti_2009_Biochem.J_421_97
PubMedSearch : Carletti_2009_Biochem.J_421_97
PubMedID: 19368529
Gene_locus related to this paper: human-BCHE

Title : Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation - Carletti_2008_J.Am.Chem.Soc_130_16011
Author(s) : Carletti E , Li H , Li B , Ekstrom F , Nicolet Y , Loiodice M , Gillon E , Froment MT , Lockridge O , Schopfer LM , Masson P , Nachon F
Ref : Journal of the American Chemical Society , 130 :16011 , 2008
Abstract : Human butyrylcholinesterase (hBChE) hydrolyzes or scavenges a wide range of toxic esters, including heroin, cocaine, carbamate pesticides, organophosphorus pesticides, and nerve agents. Organophosphates (OPs) exert their acute toxicity through inhibition of acetylcholinesterase (AChE) by phosphorylation of the catalytic serine. Phosphylated cholinesterase (ChE) can undergo a spontaneous, time-dependent process called "aging", during which the OP-ChE conjugate is dealkylated. This leads to irreversible inhibition of the enzyme. The inhibition of ChEs by tabun and the subsequent aging reaction are of particular interest, because tabun-ChE conjugates display an extraordinary resistance toward most current oxime reactivators. We investigated the structural basis of oxime resistance for phosphoramidated ChE conjugates by determining the crystal structures of the non-aged and aged forms of hBChE inhibited by tabun, and by updating the refinement of non-aged and aged tabun-inhibited mouse AChE (mAChE). Structures for non-aged and aged tabun-hBChE were refined to 2.3 and 2.1 A, respectively. The refined structures of aged ChE conjugates clearly show that the aging reaction proceeds through O-dealkylation of the P(R) enantiomer of tabun. After dealkylation, the negatively charged oxygen forms a strong salt bridge with protonated His438N epsilon2 that prevents reactivation. Mass spectrometric analysis of the aged tabun-inhibited hBChE showed that both the dimethylamine and ethoxy side chains were missing from the phosphorus. Loss of the ethoxy is consistent with the crystallography results. Loss of the dimethylamine is consistent with acid-catalyzed deamidation during the preparation of the aged adduct for mass spectrometry. The reported 3D data will help in the design of new oximes capable of reactivating tabun-ChE conjugates.
ESTHER : Carletti_2008_J.Am.Chem.Soc_130_16011
PubMedSearch : Carletti_2008_J.Am.Chem.Soc_130_16011
PubMedID: 18975951
Gene_locus related to this paper: human-BCHE , mouse-ACHE

Title : Mutant of Bungarus fasciatus acetylcholinesterase with low affinity and low hydrolase activity toward organophosphorus esters - Poyot_2006_Biochim.Biophys.Acta_1764_1470
Author(s) : Poyot T , Nachon F , Froment MT , Loiodice M , Wieseler S , Schopfer LM , Lockridge O , Masson P
Ref : Biochimica & Biophysica Acta , 1764 :1470 , 2006
Abstract : Enzymes hydrolysing highly toxic organophosphate esters (OPs) are promising alternatives to pharmacological countermeasures against OPs poisoning. Bungarus fasciatus acetylcholinesterase (BfAChE) was engineered to acquire organophosphate hydrolase (OPase) activity by reproducing the features of the human butyrylcholinesterase G117H mutant, the first mutant designed to hydrolyse OPs. The modification consisted of a triple mutation on the (122)GFYS(125) peptide segment, resulting in (122)HFQT(125). This substitution introduced a nucleophilic histidine above the oxyanion hole, and made space in that region. The mutant did not show inhibition by excess acetylthiocholine up to 80 mM. The k(cat)/K(m) ratio with acetylthiocholine was 4 orders of magnitude lower than that of wild-type AChE. Interestingly, due to low affinity, the G122H/Y124Q/S125T mutant was resistant to sub-millimolar concentrations of OPs. Moreover, it had hydrolysing activity with paraoxon, echothiophate, and diisopropyl phosphofluoridate (DFP). DFP was characterised as a slow-binding substrate. This mutant is the first mutant of AChE capable of hydrolysing organophosphates. However, the overall OPase efficiency was greatly decreased compared to G117H butyrylcholinesterase.
ESTHER : Poyot_2006_Biochim.Biophys.Acta_1764_1470
PubMedSearch : Poyot_2006_Biochim.Biophys.Acta_1764_1470
PubMedID: 16962835