Targeting Hsp27/eIF4E interaction with phenazine compound: A promising alternative for castration-resistant prostate cancer treatment

The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo

Conception, modélisation, synthèse et évaluation des propriétés antivirales de nouveaux analogues de nucléosides

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Synthèse, étude physico-chimique et activité de transfection de nouveaux amphiphiles dérivés de nucléosides

L évolution de la thérapie génique réside essentiellement dans le développement de systèmes de transfert de gène. Les vecteurs synthétiques sont apparus comme une alternative prometteuse aux problèmes rencontrés lors de l utilisation de virus comme transporteurs. Depuis quelques années, les amphiphiles dérivés de nucléosides développés au sein de notre Laboratoire sont utilisés dans le cadre d applications biologiques variées (prodrogues, transport de biomolécules d intérêt thérapeutique). Notre projet de recherche se propose de concevoir de nouveaux vecteurs de transfert de gènes. Deux familles de vecteurs ont été synthétisées : d une part des nucléolipides cationiques et d autre part des nucléolipides phosphorylés anioniques. La première famille de composés est constituée de nucléolipides avec des chaînes oléyles et une tête polaire ammonium. La synthèse de ces différents analogues a été élaborée suivant différentes variations structurales : remplacement de la base naturelle par une base universelle, modification de la partie osidique par une partie acyclique, modification de la position de la tête polaire. La deuxième famille de vecteurs est issue de la synthèse de nucléolipides phosphorylés sur la base d une approche faisant intervenir des intermédiaires de type phosphoramidite.Différentes études physico-chimiques (DLS, MET, BET) mettent en évidence la formation d organisations supramoléculaires de ces nucléolipides en milieu aqueux et leur capacité à se lier à l ADN. Le potentiel de chacun de ces composés en tant que transporteur de divers agents nucléiques (ADN, siRNA) a été évalué in vitro sur différentes lignées cellulaires. Certains lipides cationiques présentent une capacité de vectorisation du siRNA comparable voire supérieure à celle du composé de référence. Les nucléolipides anioniques se sont révélés capables de transfecter l ADN plasmidique sur des cellules Hek.The development of gene therapy is essentially based on gene transfer systems development. Considering the problems associated with viruses as delivery systems, synthetic vectors were proved to be promising alternative to viral-based systems. Our research project lies within the scope of developing new synthetic vectors for gene transfer. For many years, amphiphilic structures based on nucleosides have been used in our laboratories for several applications, including antitumoral prodrugs or drug/biomolecule delivery systems. In this work, we designed new cationic and anionic nucleolipids. Different structural modifications including base, sugar and charge modifications were envisioned. Universal base, acyclic osidic part and polar head have been incorporated in order to tune the potentiality of the original nucleolipids. The anionic phosphorylated nucleolipids have been synthesized by using a convenient phosphoramidites synthetic route. Several studies including DLS, TEM and ethidium bromide assay demonstrated that the amphiphilic molecules form supramolecular organizations and are able to bind nucleic acids. Finally, the in vitro transfection activity of the compounds was assessed on different cell lines. Cationic lipids exhibited transfection properties of siRNA comparable to or even better than, those commercially available and commonly used as references. Moreover, anionic nucleolipids exhibited a significant transfection efficiency on Hek cell lines.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Nucleoside, nucleotide and oligonucleotide based amphiphiles: a successful marriage of nucleic acids with lipids

International audienceAmphiphilic molecules based on nucleosides, nucleotides and oligonucleotides are finding more and more biotechnological applications. This Perspective highlights their synthesis, supramolecular organization as well as their applications in the field of biotechnology

Synthesis of (±) cis-substituted cyclohexenyl and cyclohexanyl nucleosides via a double Mitsunobu-type reaction

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Phosphonium-ammonium-based di-cationic ionic liquids as antibacterial over the ESKAPE group

International audienceEmergence of antibioresistance is currently a major threat of public health worldwide. Hence there is an urge need of finding new antibacterial material. Herein, we report a simple and eco-friendly method to synthesize homo and heterodicationic ionic liquids based on quaternary phosphonium and ammonium salt. In order to investigate the structure activity relationship (SAR) we measured the MICs of a series of 16 derivatives with structural variations (nature of cations and counter-ions, size of linker and alkyl side chains as well as structural symmetry) over a range of Gram-positive and Gram-negative bacterial strains from the ESKAPE group. Some of the tested structures exhibit high antimicrobial activities (MIC = 0.5 mg/L) and are active over a wide range of bacteria from Gram-positive to Gram-negative. Overall, these results reveal the strong potential of di-cationic derivatives as antibacterial agents and the determination of activities from structural features gives decisive information for future synthesis of such di-cationic structures for biocidal purpose

Antibacterial activities of mono-, di- and tri-substituted triphenylamine-based phosphonium ionic liquids

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