To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide.

Membrane disruptive α-helical antimicrobial peptides (AMPs) offer an opportunity to address multidrug resistance; however, most AMPs are toxic and unstable in serum. These limitations can be partly overcome by introducing D-residues, which often confers protease resistance and reduces toxicity without affecting antibacterial activity, presumably due to lowered α-helicity. Here, we investigated 31 diastereomers of the α-helical AMP KKLLKLLKLLL. Three diastereomers containing two, three, and four D-residues showed increased antibacterial effects, comparable hemolysis, reduced toxicity against HEK293 cells, and excellent serum stability, while another diastereomer with four D-residues additionally displayed lower hemolysis. X-ray crystallography confirmed that high or low α-helicity as measured by circular dichroism indicated α-helical or disordered structures independently of the number of chirality switched residues. In contrast to previous reports, α-helicity across diastereomers correlated with both antibacterial activity and hemolysis and revealed a complex relationship between stereochemistry, activity, and toxicity, highlighting the potential of diastereomers for property optimization

Développement d'un modèle toxicocinétique basé sur la physiologie pour la perméthrine et ses métabolites chez la rate gestante

The French biomonitoring studies have highlighted the existence of an overexposure of the general population including pregnant women to pyrethroids in comparison with other countries. Pyrethroids are neurotoxic compounds that interfere with nervous signal transmission. These compounds can cross the placental barrier, exposing the foetus during the critical period of development. Among this class of insecticides, permethrin (blend of cis and trans isomers) is the most commonly used in household applications. The aim of this thesis is to develop a gestational physiological based pharmacokinetic model in rats. To get this objective, we developed at first a LC-MS/MS method to quantify permethrin isomers and their metabolites in maternal (liver, brain, blood, kidney, fat, mammary gland, placenta, urine and faeces) and foetal matrices (liver, brain and blood). The validated method was then used to quantify our compounds of interest in a toxicokinetic study in pregnant rats. The concentrations data were then used to develop our gestational PBPK model in rats. This model could be later extrapolated to Humans to estimate maternal and foetal exposure.Les études de biosurveillance ont montré une exposition plus élevée de la population française, y compris les femmes enceintes, aux pyréthrinoïdes par rapport à d'autres pays. Les pyréthrinoïdes sont des composés neurotoxiques qui agissent sur leurs organismes cibles en interférant sur la transmission du signal nerveux. Ces composés passent la barrière placentaire exposant le fœtus durant la période sensible du développement. Au sein de cette famille d'insecticides, la perméthrine (mélange des isomères cis et trans) est le composé le plus utilisé en milieu domestique. L'objectif de ce travail de thèse est de développer un modèle toxicocinétique basé sur la physiologie (PBPK) chez la rate gestante. Pour ce faire, nous avons tout d'abord mis au point une méthode de dosage LC-MS/MS des isomères de la perméthrine et de ses métabolites dans différentes matrices maternelles (foie, cerveau, sang, rein, graisse, glande mammaire, placenta, urine et fèces) et fœtales (foie, cerveau et sang). Cette méthode a ensuite été utilisée pour doser les composés d'intérêt dans le cadre d'une étude de toxicocinétique chez la rate gestante. Un modèle PBPK gestationnel chez le rat a été développé grâce à ces données de cinétique permettant ainsi d'estimer l'exposition maternelle et fœtale durant toute la période de la gestation. Ce modèle pourra par la suite être extrapolé à l'Homme, en vue de pouvoir estimer l'exposition maternelle et fœtal

Evaluation of permethrin disposition in pregnant rats and fetuses during in utero exposure using a physiological basedpharmacokinetic (PBPK) model

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Développement d'un modèle toxicocinétique basé sur la physiologie pour la perméthrine et ses métabolites chez la rate gestante

Les études de biosurveillance ont montré une exposition plus élevée de la population française, y compris les femmes enceintes, aux pyréthrinoïdes par rapport à d'autres pays. Les pyréthrinoïdes sont des composés neurotoxiques qui agissent sur leurs organismes cibles en interférant sur la transmission du signal nerveux. Ces composés passent la barrière placentaire exposant le fœtus durant la période sensible du développement. Au sein de cette famille d'insecticides, la perméthrine (mélange des isomères cis et trans) est le composé le plus utilisé en milieu domestique. L'objectif de ce travail de thèse est de développer un modèle toxicocinétique basé sur la physiologie (PBPK) chez la rate gestante. Pour ce faire, nous avons tout d'abord mis au point une méthode de dosage LC-MS/MS des isomères de la perméthrine et de ses métabolites dans différentes matrices maternelles (foie, cerveau, sang, rein, graisse, glande mammaire, placenta, urine et fèces) et fœtales (foie, cerveau et sang). Cette méthode a ensuite été utilisée pour doser les composés d'intérêt dans le cadre d'une étude de toxicocinétique chez la rate gestante. Un modèle PBPK gestationnel chez le rat a été développé grâce à ces données de cinétique permettant ainsi d'estimer l'exposition maternelle et fœtale durant toute la période de la gestation. Ce modèle pourra par la suite être extrapolé à l'Homme, en vue de pouvoir estimer l'exposition maternelle et fœtaleThe French biomonitoring studies have highlighted the existence of an overexposure of the general population including pregnant women to pyrethroids in comparison with other countries. Pyrethroids are neurotoxic compounds that interfere with nervous signal transmission. These compounds can cross the placental barrier, exposing the foetus during the critical period of development. Among this class of insecticides, permethrin (blend of cis and trans isomers) is the most commonly used in household applications. The aim of this thesis is to develop a gestational physiological based pharmacokinetic model in rats. To get this objective, we developed at first a LC-MS/MS method to quantify permethrin isomers and their metabolites in maternal (liver, brain, blood, kidney, fat, mammary gland, placenta, urine and faeces) and foetal matrices (liver, brain and blood). The validated method was then used to quantify our compounds of interest in a toxicokinetic study in pregnant rats. The concentrations data were then used to develop our gestational PBPK model in rats. This model could be later extrapolated to Humans to estimate maternal and foetal exposure

La maladie de Menkes et son traitement par le complexe cuivre-histidine

La maladie de Menkes est une maladie génétique rare, liée à un dysfonctionnement affectant une protéine, l'ATP7A impliquée dans l'homéostasie du cuivre. Elle se manifeste par une neurodégénéréscence progressive ainsi que des anomalies au niveau des tissus conjonctifs et des cheveux. L'ensemble de ces symptômes s'explique par un déficit d'activité de nombreuses enzymes cupro-dépendantes. Á l'heure actuelle, le traitement standard consiste en des njections sous-cutanée de complexes cuivre-histidine en solution. Ce traitement améliore la symptomatologie, mais avec une grande disparité selon les patients en raison du grand nombre de mutations affectant le gène MNK et de l'âge du patient lors du début du traitement. C'est pour cette raison que la recherche de thérapetuiques complémentaires est nécessaires.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Evaluation of Placental Transfer and Tissue Distribution of cis- and Trans-Permethrin in Pregnant Rats and Fetuses Using a Physiological-Based Pharmacokinetic Model

International audienceBiomonitoring studies have highlighted the exposure of pregnant women to pyrethroids based on the measurement of their metabolites in urine. Pyrethroids can cross the placental barrier and be distributed in the fetus as some pyrethroids were also measured in the meconium of newborns. Prenatal exposure to pyrethroids is suspected to alter the neurodevelopment of children, and animal studies have shown that early life exposure to permethrin, one of the most commonly used pyrethroid in household applications, can alter the brain development. This study aimed to characterize the fetal permethrin exposure throughout gestation in rats. We developed a pregnancy physiologically based pharmacokinetic (pPBPK) model that describes the maternal and fetal kinetics of the cis - and trans - isomers of permethrin during the whole gestation period. Pregnant Sprague–Dawley rats were exposed daily to permethrin (50 mg/kg) by oral route from the start of gestation to day 20. Permethrin isomers were quantified in the feces, kidney, mammary gland, fat, and placenta in dams and in both maternal and fetal blood, brain, and liver. Cis - and trans -permethrin were quantified in fetal blood and tissues, with higher concentrations for the cis -isomer. The pPBPK model was fitted to the toxicokinetic maternal and fetal data in a Bayesian framework. Several parameters were adjusted, such as hepatic clearances, partition coefficients, and intestinal absorption. Our work allowed to estimate the prenatal exposure to permethrin in rats, especially in the fetal brain, and to quantitatively estimate the placental transfer. These transfers could be extrapolated to humans and be incorporated in a human pPBPK model to estimate the fetal exposure to permethrin from biomonitoring data

Evaluation of permethrin disposition in pregnant rats and fetuses during in utero exposure using a physiological based pharmacokinetic (PBPK) model

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PBPK modeling to support risk assessment of pyrethroid exposure in French pregnant women

International audienceBackgroundPyrethroids are widely used pesticides and are suspected to affect children's neurodevelopment. The characterization of pyrethroid exposure during critical windows of development, such as fetal development and prenatal life, is essential to ensure a better understanding of pyrethroids potential effects within the concept of Developmental Origins of Health and Disease.ObjectiveThe aim of this study was to estimate maternal exposure of French pregnant women from biomonitoring data and simulate maternal and fetal internal concentrations of 3 pyrethroids (permethrin, cypermethrin and deltamethrin) using a multi-substance pregnancy-PBPK (physiologically based pharmacokinetics) model. The estimated maternal exposures were compared to newly proposed toxicological reference values (TRV) children specific also called draft child-specific reference value to assess pyrethroid exposure risk during pregnancy i.e. during the in utero exposure period.MethodsA pregnancy-PBPK model was developed based on an existing adult pyrethroids model. The maternal exposure to each parent compound of pregnant women of the Elfe (French Longitudinal Study since Childhood) cohort was estimated by reverse dosimetry based on urinary biomonitoring data. To identify permethrin and cypermethrin contribution to their common urinary biomarkers of exposure, an exposure ratio based on biomarkers in hair was tested. Finally, exposure estimates were compared to current and draft child-specific reference values derived from rodent prenatal and postnatal exposure studies.ResultsThe main contributor to maternal pyrethroid diet intake is cis-permethrin. In blood, total internal concentrations main contributor is deltamethrin. In brain, the major contributors to internal pyrethroid exposure are deltamethrin for fetuses and cis-permethrin for mothers. Risk is identified only for permethrin when referring to the draft child-specific reference value. 2.5% of the population exceeded permethrin draft child-specific reference value.ConclusionsA new reverse dosimetry approach using PBPK model combined with human biomonitoring data in urine and hair was proposed to estimate Elfe pregnant population exposure to a pyrethroids mixture with common metabolites