101 research outputs found
A liquid crystalline phase in spermidine-condensed DNA
Over a large range of salt and spermidine concentrations, short DNA fragments precipitated by spermidine (a polyamine) sediment in a pellet from a dilute isotropic supernatant. We report here that the DNA-condensed phase consists of a cholesteric liquid crystal in equilibrium with a more concentrated phase. These results are discussed according to Flory's theory for the ordering of rigid polymers. The liquid crystal described here corresponds to an ordering in the presence of attractive interactions, in contrast with classical liquid crystalline DNA. Polyamines are often used in vitro to study the functional properties of DNA. We suggest that the existence of a liquid crystalline state in spermidine-condensed DNA is relevant to these studies
Drug development in oncology assisted by noninvasive optical imaging.
International audienceEarly and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology
Binding of the chemokine CXCL12α to its natural extracellular matrix ligand heparan sulfate enables myoblast adhesion and facilitates cell motility
The chemokine CXCL12α is a potent chemoattractant that guides the migration of muscle precursor cells (myoblasts) during myogenesis and muscle regeneration. To study how the molecular presentation of chemokines influences myoblast adhesion and motility, we designed multifunctional biomimetic surfaces as a tuneable signalling platform that enabled the response of myoblasts to selected extracellular cues to be studied in a well-defined environment. Using this platform, we demonstrate that CXCL12α, when presented by its natural extracellular matrix ligand heparan sulfate (HS), enables the adhesion and spreading of myoblasts and facilitates their active migration. In contrast, myoblasts also adhered and spread on CXCL12α that was quasi-irreversibly surface-bound in the absence of HS, but were essentially immotile. Moreover, co-presentation of the cyclic RGD peptide as integrin ligand along with HS-bound CXCL12α led to enhanced spreading and motility, in a way that indicates cooperation between CXCR4 (the CXCL12α receptor) and integrins (the RGD receptors). Our findings reveal the critical role of HS in CXCL12α induced myoblast adhesion and migration. The biomimetic surfaces developed here hold promise for mechanistic studies of cellular responses to different presentations of biomolecules. They may be broadly applicable for dissecting the signalling pathways underlying receptor cross-talks, and thus may guide the development of novel biomaterials that promote highly specific cellular responses
2-Hydroxy-4-methoxybenzyl as a Thiol-Protecting Group for Directed-Disulfide Bond Formation
International audienceThe chemical synthesis of disulfide-rich peptides such as toxins can be accomplished by using numerous orthogonal cysteine-protecting groups. Herein we report the use of Hmb off/on protecting group for directed disulfide bond formation. Its combination with classical Trt, Acm and Mob groups was studied for the synthesis of NMB-1 and Phlotoxin-1 toxins highlighting new orthogonal strategies for directed disulfide bond formation
Multimeric RGD-Based Strategies for Selective Drug Delivery to Tumor Tissues
RGD peptides have received a lot of attention over the two last decades, in particular to improve tumor therapy through the targeting of the αVβ3 integrin receptor. This review focuses on the molecular design of multimeric RGD compounds, as well as the design of suitable linkers for drug delivery. Many examples of RGD–drug conjugates have been developed, and we show the importance of RGD constructs to enhance binding affinity to tumor cells, as well as their drug uptake. Further, we also highlight the use of RGD peptides as theranostic systems, promising tools offering dual modality, such as tumor diagnosis and therapy. In conclusion, we address the challenging issues, as well as ongoing and future development, in comparison with large molecules, such as monoclonal antibodies
Multimeric RGD-Based Strategies for Selective Drug Delivery to Tumor Tissues
RGD peptides have received a lot of attention over the two last decades, in particular to improve tumor therapy through the targeting of the αVβ3 integrin receptor. This review focuses on the molecular design of multimeric RGD compounds, as well as the design of suitable linkers for drug delivery. Many examples of RGD–drug conjugates have been developed, and we show the importance of RGD constructs to enhance binding affinity to tumor cells, as well as their drug uptake. Further, we also highlight the use of RGD peptides as theranostic systems, promising tools offering dual modality, such as tumor diagnosis and therapy. In conclusion, we address the challenging issues, as well as ongoing and future development, in comparison with large molecules, such as monoclonal antibodies
Biomolecular Assemblies Combining Two Orthogonal Copper-Mediated Ligations in a One-Pot Reaction
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Caractérisation des interactions biomoléculaires entre des ligands peptidiques immobilisés sur une surface et des récepteurs cellulaires
L'objectif visé dans cette étude consiste à développer une méthodologie de caractérisation des interactions ligands/récepteurs cellulaires à la surface d'un transducteur physique. Le ligand immobilisé est représenté par un cyclopentapeptide c(-RGDfK-) dont les propriétés de reconnaissance spécifique pour l'intégrine alphaV beta3 sont bien connues. Les travaux de thèse présentés dans ce manuscrit concernent la synthèse des ligands peptidiques, la mise au point des différentes techniques d'immobilisation de ces ligands et enfin la caractérisation des interactions biomoléculaires avec des cellules exprimant l'intégrine. Le ligand peptidique est présenté de façon multivalente sur un châssis moléculaire cyclodécapeptidique de séquence c(-Pro-Gly-Lys-Lys-Lys-)2. Le greffage des différents motifs se fait via la formation d'un lien éther d'oxime ou d'un lien amide sur les chaînes latérales des lysines orientées de part et d'autre du plan moyen du cyclopeptide. Trois approches ont été mises en œuvre pour fixer les ligands -RGD- sur une surface : le couplage affin, l'insertion dans une bicouche lipidique et le couplage covalent. Les surfaces fonctionnelles résultantes ont été caractérisées par des méthodes physico-chimiques d'analyse de surface et d'interface. Des tests d'adhésion cellulaire, suivis par QCM-D et par microscopie optique, ont ensuite permis de caractériser les propriétés de reconnaissance des ligands peptidiques. La comparaison des signaux de QCM-D et des images de la surface, obtenus à différents taux de greffage du ligand a permis d'identifier une densité de greffage minimale en ligand nécessaire à l'adhésion et à l'étalement des cellules.The aim of this study is to develop a methodology for characterizing ligand/cellular receptor interaction through the immobilization of the ligand on the surface of a physical transducer. The recognition element is based on a cyclopentapeptide c(-RGDfK-) whose specific recognition properties for the avb3 integrin are well known. Herein, we described the synthesis of peptide ligands, the different techniques of ligand immobilization, and finally the characterization of the biomolecular interactions with cells that express the integrin. A cyclic decapeptide sequence c(-Pro-Gly-Lys-Lys-Lys-)2 is used as a scaffold for the multivalent presentation of peptide ligands. Grafting of the different elements was carried out by way of oxime or amide bond at the lysine side chains on each side of the cyclopeptide. Three approaches were used to graft -RGD- ligands on a surface: a binding by the use of biotin-streptavidin interaction, inclusion of a lipopeptide ligand into a lipid bilayer, and through a covalent coupling. The resulting functional surfaces were characterized by physicochemical analysis of surface and interface. Cell adhesion experiments were conducted by using QCM-D and optical microscopy in order to characterize the recognition properties of peptide ligands. The comparison of the QCM-D signals and surface images obtain for different ligand grafted densities on the surface permit to estimate the minimum ligand concentrations required for cell attachment and cell spreading.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF
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