Landry C

References (6)

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 : Biological markers to establish a relationship between the health status of the St. Lawrence River yellow perch (Perca flavescens) with a gradient of anthropogenic disturbances - Landry_2020_Sci.Total.Environ_726_138515
Author(s) : Landry C , Houde M , Brodeur P , Boily M
Ref : Sci Total Environ , 726 :138515 , 2020
Abstract : Since the mid-1990s, the decline of the yellow perch population of Lake Saint-Pierre (hereinafter LSP) in Quebec, Canada has been the subject of several research programs. The combined effect of habitat deterioration, the presence of invasive species, and poor water quality negatively affected the yellow perch population in this lake. In 2013, we sampled yellow perch (larvae, juveniles and adults) at six sites along the St. Lawrence River representing a gradient of increasing human influences from upstream to downstream and measured several biomarkers including retinoid compounds (vitamin A). In the most contaminated sites (LSP, north and south shores), we found that retinoid stores were decreased in all three stages of development. To corroborate these results and to test other biomarkers, we once again sampled yellow perch (adults only) from the same sites. Results from our 2014 and 2015 samplings confirmed that LSP yellow perch appeared to be at a disadvantage compared to fish from upstream populations. Individuals from LSP have lower acetylcholinesterase (AChE) activity as well as lower retinoid levels in liver and plasma. These fish were also marked by lower levels of antioxidants such as lycopene and vitamin E. A discriminant analysis of this set of results confirmed that the yellow perch of the LSP could be easily discriminated from those of the other sites (2014 and 2015) on the basis of liver retinoid and, to a lesser extent, of the liver tocopherol and protein concentration of the muscle, as well as AChE activity and DROH (all-trans-3,4-dehydroretinol) measured in plasma.
ESTHER : Landry_2020_Sci.Total.Environ_726_138515
PubMedSearch : Landry_2020_Sci.Total.Environ_726_138515
PubMedID: 32481216

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 : 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 : Interactive effects of neonicotinoids and natural ultraviolet radiation on yellow perch (Perca flavescens) larvae - Paquet-Walsh_2019_Sci.Total.Environ_685_690
Author(s) : Paquet-Walsh A , Bertolo A , Landry C , Deschamps L , Boily M
Ref : Sci Total Environ , 685 :690 , 2019
Abstract : Neonicotinoids (NEOCs) are insecticides that are widely used worldwide in the culture of maize and soya. Whereas they specifically target terrestrial insects by acting as agonists of the neurotransmitter acetylcholine in their nervous system, their effects on the cholinergic system of vertebrates is still unclear. Moreover, there is an increasing concern about their effects on aquatic biota because of their high leaching potential. In the agricultural watershed of Lake St. Pierre (LSP) (St. Lawrence River System, Quebec, Canada), for example, NEOC concentrations considered toxic for aquatic biota (>8.3ngL(-1)) have frequently been detected. These conditions may affect the yellow perch (Perca flavescens) population in LSP, which collapsed in the mid 1990s and is now experiencing poor recruitment. Moreover, because their larvae are found in shallow waters (<80cm) near agricultural land, they are also exposed to ultraviolet radiation (UVR), with unknown potential interactions with NEOCs. The objective of this study was to test the synergistic effects of two commonly used NEOCs (imidacloprid and thiamethoxam) with natural UVR on yellow perch larvae using survival analysis and biomarkers to better quantify lethal and sublethal effects. Three common garden experiments were conducted with thiamethoxam and/or imidacloprid and natural UVR following a factorial design. Our results showed an interaction between UVR and thiamethoxam in terms of larval mortality. At the sublethal level, imidacloprid was associated with increased protein content and, in the presence of UVR, with increased acetylcholinesterase activity, thus indicating a cholinergic perturbation like that found in insects. Finally, we also found unexpected reduced lipid peroxidation associated with imidacloprid. A reduction in the overall lipid accumulation is suspected to be behind this puzzling result. These results will open new research avenues related to the effects of NEOCs on proteins and lipid accumulation.
ESTHER : Paquet-Walsh_2019_Sci.Total.Environ_685_690
PubMedSearch : Paquet-Walsh_2019_Sci.Total.Environ_685_690
PubMedID: 31203163

Title : Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain - Brindisi_2016_J.Med.Chem_59_2612
Author(s) : Brindisi M , Maramai S , Gemma S , Brogi S , Grillo A , Di Cesare Mannelli L , Gabellieri E , Lamponi S , Saponara S , Gorelli B , Tedesco D , Bonfiglio T , Landry C , Jung KM , Armirotti A , Luongo L , Ligresti A , Piscitelli F , Bertucci C , Dehouck MP , Campiani G , Maione S , Ghelardini C , Pittaluga A , Piomelli D , Di Marzo V , Butini S
Ref : Journal of Medicinal Chemistry , 59 :2612 , 2016
Abstract : We report the discovery of compound 4a, a potent beta-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.
ESTHER : Brindisi_2016_J.Med.Chem_59_2612
PubMedSearch : Brindisi_2016_J.Med.Chem_59_2612
PubMedID: 26888301