A5011412856- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Pesticide Exposure and Toxicity
- Chemical synthesis and alkaloids
- Pesticide and Herbicide Environmental Studies
- Environmental Toxicology and Ecotoxicology
- Insect and Pesticide Research
- Enzyme function and inhibition
- Chemical Reaction Mechanisms
- Phosphodiesterase function and regulation
- Inorganic and Organometallic Chemistry
- Medicinal Plants and Neuroprotection
- Nicotinic Acetylcholine Receptors Study
- bioluminescence and chemiluminescence research
- Analytical Methods in Pharmaceuticals
- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Monoclonal and Polyclonal Antibodies Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Biotin and Related Studies
- Protein Structure and Dynamics
- Synthesis and biological activity
- Radiopharmaceutical Chemistry and Applications
- Toxic Organic Pollutants Impact
- Crystallization and Solubility Studies
Institut de Médecine Tropicale du Service de Santé des Armées
2014-2024
DGA Partners
2023
Institut de Biologie Structurale
2005-2017
Université Grenoble Alpes
2005-2016
Association pour la Recherche en Physiologie de l’Environnement
2016
Centre National de la Recherche Scientifique
1998-2014
Commissariat à l'Énergie Atomique et aux Énergies Alternatives
2008-2014
Université Joseph Fourier
2008-2014
CEA Grenoble
2008-2014
Institut Laue-Langevin
2014
Cholinesterases are among the most efficient enzymes known. They divided into two groups: acetylcholinesterase, involved in hydrolysis of neurotransmitter acetylcholine, and butyrylcholinesterase unknown function. Several crystal structures former have shown that active site is located at bottom a deep narrow gorge, raising question how substrate products enter leave. Human (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus...
The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components the pathology, like cholinergic dysfunction and amyloid aggregation. Such are usually basis cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a target. To aid in design these MTDLs, we report crystal structures hAChE (human acetylcholinesterase) complex FAS-2 (fasciculin 2) hydroxylated derivative huprine (huprine W),...
Since the September 11, 2001, terrorist attacks in United States, specter of a chemical threat against civilian populations has renewed research interest warfare agents, their mechanisms action, and treatments that reverse effects. In this Account, we focus specifically on organophosphorus nerve agents (OPNAs). Although some OPNAs are used as pest control, most toxic chemicals class armed conflicts. The acute toxicity results from irreversible inhibition acetylcholinesterase (AChE, EC...
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in number aromatic residues lining active site gorge, which leads large shape gorge potentially distinct interactions with an individual ligand....
Abstract Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes the termination neurotransmission. Its enzymatic activity increases with progression, thus classifying BChE as a viable therapeutic target advanced AD. Potent, selective reversible human inhibitors were developed. The solved crystal...
Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 identified as a highly submicromolar inhibitor (huBuChE IC50 = 0.443 μM) with high permeability the PAMPA-BBB model. The X-ray crystal structure huBuChE complex revealed atomic-level interactions and offers opportunities for further development series.
The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with progression Alzheimer's disease, thus classifying BChE as a promising drug target advanced disease. We used structure-based discovery approaches to develop potent, selective, and reversible human inhibitors. most compound 3, had picomolar inhibition constant versus due strong cation-π interactions, revealed by solved crystal structure its complex BChE. Additionally, 3 inhibits ex vivo is noncytotoxic. In vitro...
The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack effective drugs as well basis development "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there need new that are not only but also accessible. With this motivation, we report first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied framework combination functionalized CNSL components and...
Tryptophan-derived selective nanomolar butyrylcholinesterase inhibitors with great potential for symptomatic therapy against Alzheimer's disease are disclosed.
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) monoamine oxidases (hMAO-A/B) for therapy neurodegenerative diseases. identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly...
The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after use chemical weapons (chlorine, phosgene) on battlefield World War I. Despite Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, target nervous system inhibiting acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated...
Human butyrylcholinesterase (BChE; EC 3.1.1.8) is of particular interest because it hydrolyzes or scavenges a wide range toxic compounds including cocaine, organophosphorus pesticides and nerve agents. The relative contribution each N‐linked glycan for the solubility, stability secretion enzyme was investigated. A recombinant monomeric BChE lacking four out nine N‐glycosylation sites C‐terminal oligomerization domain stably expressed as monomer in CHO cells. purified showed catalytic...
Human butyrylcholinesterase (hBChE) hydrolyzes or scavenges a wide range of toxic esters, including heroin, cocaine, carbamate pesticides, organophosphorus and nerve agents. Organophosphates (OPs) exert their acute toxicity through inhibition acetylcholinesterase (AChE) by phosphorylation the catalytic serine. Phosphylated cholinesterase (ChE) can undergo spontaneous, time-dependent process called "aging", during which OP-ChE conjugate is dealkylated. This leads to irreversible enzyme. The...
Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on tabun adduct, leading to an "aged" enzyme, resistant oxime reactivators. The aging may proceed via either dealkylation or deamidation, depending stereochemistry phosphoramidyl adduct. We solved X-ray structure aged tabun−hAChE complexed with fasciculin II, and we show proceeds through O-dealkylation, in agreement mechanism determined...
Human plasma and fatty acid free human albumin were incubated with soman at pH 8.0 25 °C. Four methods used to monitor the reaction of soman: progressive inhibition aryl acylamidase activity albumin, release fluoride ion from soman, 31P NMR, mass spectrometry. Inhibition (phosphonylation) was slow a bimolecular rate constant 15 ± 3 M−1 min−1. MALDI-TOF tandem spectrometry soman−albumin adduct showed that phosphonylated on tyrosine 411. No secondary dealkylation (aging) occurred. Covalent...
Butyrylcholinesterase (BChE) is a serine hydrolase that present in all mammalian tissues. It can accommodate larger substrates or inhibitors than acetylcholinesterase (AChE), the enzyme responsible for hydrolysis of neurotransmitter acetylcholine central nervous system and neuromuscular junctions. AChE specific target organophosphorous pesticides warfare nerve agents, BChE stoichiometric bioscavenger. Conversion into catalytic bioscavenger by rational design designing reactivators to...
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 a superior or similar in vitro ability to reactivate the enzyme as compared that of HI-6, obidoxime, TMB-4 and HLö-7.
The combination of the scaffolds cholinesterase inhibitor huprine Y and antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) butyrylcholinesterase (BChE) that retain or improve properties capsaicin. Crystal structures their complexes AChE BChE revealed molecular basis for high potency. Brain penetration was confirmed by biodistribution studies C57BL6 mice, one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic...
Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, bound OP undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves residues His438 and Glu197 that are proximal (Ser198). mechanism is known in detail for nerve gases soman, sarin, tabun well pesticide metabolite isomalathion....