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Nguyen P.N.,Charles Sadron Institute | Waton G.,Charles Sadron Institute | Vandamme T.,CNRS Laboratory of Design and Application of Bioactive Molecules | Krafft M.P.,Charles Sadron Institute
Angewandte Chemie - International Edition | Year: 2013

Prolonged periodical variations of the surface density of a film of phospholipids adsorbed on the surface of an air bubble and in contact with a dispersion of phospholipid vesicles (orange) lead to accelerated phospholipid adsorption and lowering of the interfacial tension. The phenomenon is assigned to a coupling between the periodical variation of the surface density of the phospholipid at the interface and its dilute-to-condensed (LE-to-LC) phase transition. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Jiang R.,CNRS Laboratory of Design and Application of Bioactive Molecules | Taly A.,University Pierre and Marie Curie | Grutter T.,CNRS Laboratory of Design and Application of Bioactive Molecules
Trends in Biochemical Sciences | Year: 2013

P2X receptors are nonselective cation channels gated by extracellular ATP. They represent new therapeutic targets, and they form channels with a unique trimeric architecture. In 2009, the first crystal structure of a P2X receptor was reported, in which the receptor was in an ATP-free, closed channel state. However, our view recently changed when a second crystal structure was reported, in which a P2X receptor was bound to ATP and resolved in an open channel conformation. This remarkable structure not only confirms many key experimental data, including the recent mechanisms of ATP binding and ion permeation, but also reveals unanticipated mechanisms. Certainly, this new information will accelerate our understanding of P2X receptor function and pharmacology at the atomic level. © 2012 Elsevier Ltd.


Li X.,CNRS Laboratory of Design and Application of Bioactive Molecules
International journal of nanomedicine | Year: 2011

Nanoemulsions consist of very stable nanodroplets of oil dispersed in an aqueous phase, typically below 300 nm in size. They can be used to obtain a very fine, homogeneous dispersion of lipophilic compounds in water, thus facilitating their handling and use in nanomedicine. However, the drawback is that they are suspended in an aqueous media. This study proposes a novel technique for drying lipid nanoemulsion suspensions to create so-called Trojan particles, ie, polymer microparticles (around 2 μm) which very homogeneously "entrap" the nano-oil droplets (around 150 nm) in their core. Microencapsulation of the nanoemulsions was performed using a spray-drying process and resulted in a dried powder of microparticles. By using a low-energy nanoemulsification method and relatively gentle spray-drying, the process was well suited to sensitive molecules. The model lipophilic molecule tested was vitamin E acetate, encapsulated at around 20% in dried powder. We showed that the presence of nanoemulsions in solution before spray-drying had a significant impact on microparticle size, distribution, and morphology. However, the process itself did not destroy the oil nanodroplets, which could easily be redispersed when the powder was put back in contact with water. High-performance liquid chromatography follow-up of the integrity of the vitamin E acetate showed that the molecules were intact throughout the process, as well as when conserved in their dried form. This study proposes a novel technique using a spray-drying process to microencapsulate nanoemulsions. The multiscale object formed, so-called Trojan microparticles, were shown to successfully encapsulate, protect, and release the lipid nanodroplets.


King M.,CNRS Laboratory of Design and Application of Bioactive Molecules | Wagner A.,CNRS Laboratory of Design and Application of Bioactive Molecules
Bioconjugate Chemistry | Year: 2014

In response to the ever increasing need of chemical biology for new tools, a wide variety of new, highly selective reactions have been described. Herein we report a summary of recent developments and the historical background on bioorthogonal ligation reactions. © 2014 American Chemical Society.


Jiang R.,CNRS Laboratory of Design and Application of Bioactive Molecules
Channels (Austin, Tex.) | Year: 2012

The molecular mechanism underlying channel opening in response to agonist binding remains a challenging issue in neuroscience. In this regard, many efforts have been recently undertaken in ATP-gated P2X receptors. Among those efforts, we have provided evidence in the P2X2 receptor that tightening of ATP sites upon agonist binding induces opening of the ion channel. Here we extend our analysis to show that the sulfhydryl-reactive ATP analog 8-thiocyano-ATP (NCS-ATP), a potent P2X2 agonist, when covalently labeled in the ATP-binding site at position Leu186 likely favors the tightening mechanism, but not the channel opening mechanism. Our data predict the existence of intermediate or preactivation state(s) trapped by NCS-ATP, in which tightening of the binding site is favored while the channel is still closed. We propose that this (these) intermediate ATP-bound state(s) prime(s) channel gating in the P2X2 receptor.


Leriche G.,CNRS Laboratory of Design and Application of Bioactive Molecules | Chisholm L.,CNRS Laboratory of Design and Application of Bioactive Molecules | Wagner A.,CNRS Laboratory of Design and Application of Bioactive Molecules
Bioorganic and Medicinal Chemistry | Year: 2012

Interest in cleavable linkers is growing due to the rapid development and expansion of chemical biology. The chemical constrains imposed by the biological conditions cause significant challenges for organic chemists. In this review we will present an overview of the cleavable linkers used in chemical biology classified according to their cleavage conditions by enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, oxidizing reagents. © 2010 Elsevier Ltd. All rights reserved.


Foillard S.,CEA Saclay Nuclear Research Center | Zuber G.,CNRS Laboratory of Design and Application of Bioactive Molecules | Doris E.,CEA Saclay Nuclear Research Center
Nanoscale | Year: 2011

Carbon nanotubes (CNTs) covalently modified with low molecular weight polyethylenimine (PEI) are able to bind and deliver siRNA to cells with higher efficacy than a reference lipidic carrier. The performances of the nanohybrid are rationalized by the combination of the cell penetration and endosomal escape properties of CNTs and PEI, respectively. © 2011 The Royal Society of Chemistry.


Vandamme T.,CNRS Laboratory of Design and Application of Bioactive Molecules
Journal of Pharmacy and Bioallied Sciences | Year: 2014

Advances in molecular biology have significantly increased the understanding of the biology of different diseases. However, these discoveries have not yet been fully translated into improved treatments for patients with diseases such as cancers. One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. In this brief review, we will discuss the advantages and disadvantages of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases in the mouse and the preclinical studies that have already been undertaken. We will also discuss how recent improvements in imaging technologies may increase the information derived from using these GEMs during early assessments of potential therapeutic pathways. Furthermore, it is interesting to note that one of the values of using a mouse model is the very rapid turnover rate of the animal, going through the process of birth to death in a very short timeframe relative to that of larger mammalian species.


Koniev O.,CNRS Laboratory of Design and Application of Bioactive Molecules | Wagner A.,CNRS Laboratory of Design and Application of Bioactive Molecules
Chemical Society Reviews | Year: 2015

Bioconjugation methodologies have proven to play a central enabling role in the recent development of biotherapeutics and chemical biology approaches. Recent endeavours in these fields shed light on unprecedented chemical challenges to attain bioselectivity, biocompatibility, and biostability required by modern applications. In this review the current developments in various techniques of selective bond forming reactions of proteins and peptides were highlighted. The utility of each endogenous amino acid-selective conjugation methodology in the fields of biology and protein science has been surveyed with emphasis on the most relevant among reported transformations; selectivity and practical use have been discussed. This journal is © The Royal Society of Chemistry.


Lemoine D.,CNRS Laboratory of Design and Application of Bioactive Molecules | Jiang R.,CNRS Laboratory of Design and Application of Bioactive Molecules | Taly A.,University Pierre and Marie Curie | Chataigneau T.,CNRS Laboratory of Design and Application of Bioactive Molecules | And 2 more authors.
Chemical Reviews | Year: 2012

A study was conducted to demonstrate that ligand-gated ion channels (LGIC) provided significant information about neurological disorders and ligand recognition. Genome and cDNA sequencing analyses revealed that there were three major unrelated vertebrate superfamilies of LGICs, each folded with a unique architecture. The third superfamily of LGICs was composed by the excitatory ATP-gated P2X receptors. ATP-gated P2X receptors were found to be involved in several diseases, including neurodegenerative disorders. Some of these diseases included Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, hyperekplexia, and neuropathic pain, which were characterized by major LGIC dysfunctions. AD was a neurodegenerative disorder that was characterized by progressive cognitive decline, accompanied by the loss of neurons and synapses, especially the cholinergic synapses in the basal forebrain, cerebral cortex, and hippocampus.

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