The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

Year in review in Intensive Care Medicine 2010: III. ARDS and ALI, mechanical ventilation, noninvasive ventilation, weaning, endotracheal intubation, lung ultrasound and paediatrics

SCOPUS: re.jinfo:eu-repo/semantics/publishe

NGPLS : Algorithme Génétique Nicheur couplé à la Projection en Structures Latentes. Un nouvel outil de constructions de relations structure-activité quantitatives. Applications pharmaceutiques aux domaines de l'oncologie et du système nerveux central

Une solution souvent utilisée dans la littérature pour la sélection de variables et la construction de relations structure-activité quantitatives est le couplage d'un algorithme génétique simple (GA) plus ou moins modifié avec la projection en structures latentes (GAPLS). L'espace des relations structure-activité quantitatives est un espace à optima multiples sur lequel nous avons montré que la GAPLS est un outil peu performant. Nous avons donc envisagé une solution alternative à la GAPLS sachant que la poly-optimalité de l'espace de recherche et la découverte de modèles QSAR plus prédictifs sont les deux sources de difficulté qui ont motivé nos travaux. Nous avons proposé un nouvel algorithme NGPLS basé sur un algorithme génétique nicheur couplé à la PLS qui a la particularité de promouvoir une diversité utile en formant des niches écologiques dans l'espace de recherche formé par la fonction objective. Nous avons démontré sur des matrices QSAR de références que la NGPLS permet systématiquement d'identifier et de maintenir des modèles QSAR plus performants et plus divers que la GAPLS. La NGPLS est en revanche plus lente. Nous avons également montré que la NGPLS peut introduire un effet de coopération entre des modèles QSAR performants pour produire des modèles plus prédictifs. Enfin, nous avons abordé deux applications pharmaceutiques touchant à l'oncologie et au système nerveux central. Dans la première étude portant sur des inhibiteurs (BPHI, benzo[f]perhydroisoindole) de la farnésyl transférase et la seconde sur le passage de la barrière hémato-encéphalique, la NGPLS a permis d'identifier des modèles QSAR plus prédictifs que ceux proposés par la GAPLS. Enfin, nous avons proposé une nouvelle approche QSAR combinant un plan d'expériences D-optimal, la PLS et une projection en composantes principales qui s'est révélée comme la NGPLS être un outil d'aide à la décision efficace dans le procédé d'optimisation d'un nouveau médicament.AIX-MARSEILLE3-BU Sc.St Jérô (130552102) / SudocSudocFranceF

Influence des passages du virus de l'Influenza-H9N2 par des organismes aviaires et mammifères sur l'adaptabilité de sa pathogénicité et sur les mutations impliquées

COMPIEGNE-BU (601592101) / SudocSudocFranceF

Semi-automated optimized method to isolate CRISPR/Cas9 edited human pluripotent stem cell clones

International audienceAbstract Background CRISPR/Cas9 editing systems are currently used to generate mutations in a particular gene to mimic a genetic disorder in vitro. Such “disease in a dish” models based on human pluripotent stem cells (hPSCs) offer the opportunity to have access to virtually all cell types of the human body. However, the generation of mutated hPSCs remains fastidious. Current CRISPR/Cas9 editing approaches lead to a mixed cell population containing simultaneously non-edited and a variety of edited cells. These edited hPSCs need therefore to be isolated through manual dilution cloning, which is time-consuming, labor intensive and tedious. Methods Following CRISPR/Cas9 edition, we obtained a mixed cell population with various edited cells. We then used a semi-automated robotic platform to isolate single cell-derived clones. Results We optimized CRISPR/Cas9 editing to knock out a representative gene and developed a semi-automated method for the clonal isolation of edited hPSCs. This method is faster and more reliable than current manual approaches. Conclusions This novel method of hPSC clonal isolation will greatly improve and upscale the generation of edited hPSCs required for downstream applications including disease modeling and drug screening. Graphical Abstrac

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria