9 research outputs found
Dill extract induces elastic fiber neosynthesis and functional improvement in the ascending aorta of aged mice with reversal of age-dependent cardiac hypertrophy and involvement of lysyl oxidase-like-1
Elastic fibers (90% elastin, 10% fibrillin-rich microfibrils) are synthesized only in early life and adolescence mainly by the vascular smooth muscle cells through the cross-linking of its soluble precursor, tropoelastin. Elastic fibers endow the large elastic arteries with resilience and elasticity. Normal vascular aging is associated with arterial remodeling and stiffening, especially due to the end of production and degradation of elastic fibers, leading to altered cardiovascular function. Several pharmacological treatments stimulate the production of elastin and elastic fibers. In particular, dill extract (DE) has been demonstrated to stimulate elastin production in vitro in dermal equivalent models and in skin fibroblasts to increase lysyl oxidase-like-1 (LOXL-1) gene expression, an enzyme contributing to tropoelastin crosslinking and elastin formation. Here, we have investigated the effects of a chronic treatment (three months) of aged male mice with DE (5% or 10
Synthesis and pharmacological evaluation of new biomimetic peptides and benzothiadiazins
Les canaux potassiques sensibles Ă lâATP (KATP) jouent un rĂŽle primordial dans plusieurs processus cellulaires. La modulation de ces canaux par des molĂ©cules activatrices constituerait des applications pharmacologiques et mĂ©dicinales trĂšs intĂ©ressantes. Ă cet effet nous avons conçu et synthĂ©tisĂ© de nouvelles molĂ©cules hybrides cromakalim-diazoxide et diazoxide-amine/aminoacide. Nous avons Ă©galement, Ă©valuĂ© lâactivitĂ© myorelaxante de ces composĂ©s sur lâaorte de rates. Les rĂ©sultats obtenus ne montrent pas un effet myorelaxant significatif. Des Ă©tudes sur dâautres tissus, notamment les cellules ÎČ pancrĂ©atiques et le muscle utĂ©rin, sont envisagĂ©es afin dâexplorer une Ă©ventuelle sĂ©lectivitĂ© tissulaire. Par ailleurs, les interactions protĂ©ine-protĂ©ine jouent un rĂŽle fondamental dans presque tous les processus cellulaires. Elles sont fortement impliquĂ©es dans la formation de la structure dimĂ©rique de la protĂ©ase du VIH-1 et lâagrĂ©gation du peptide ÎČ amyloĂŻde impliquĂ©e dans la maladie dâAlzheimer. Lâinhibition de ces interactions serait donc dâun avantage thĂ©rapeutique pour le traitement du SIDA et de la maladie dâAlzheimer. Nous avons conçu et synthĂ©tisĂ© dâune part, des pinces molĂ©culaires Ă base de motifs carbonylhydrazides et oligohydrazides (Azatide), et dâautre part, des molĂ©cules pentapeptidiques avec un peudoaminoacide central alcoolfluorĂ©. Enfin, nous avons testĂ© la capacitĂ© des pinces molĂ©culaires Ă perturber le feuillet ÎČ terminal de la PR du VIH-1 afin d'inhiber sa dimĂ©risation et donc son activitĂ©. Nous avons rĂ©alisĂ© de mĂȘme une Ă©tude de relation structure-activitĂ© et dâaprĂšs lâensemble des rĂ©sultats obtenus, il semblerait que la flexibilitĂ© est dĂ©lĂ©tĂšre pour lâactivitĂ© inhibitrice. Nous avons Ă©galement Ă©valuĂ© la capacitĂ© des nouvelles molĂ©cules peptidomimĂ©tiques alcool fluorĂ©es Ă accĂ©lĂ©rer ou inhiber lâagrĂ©gation du peptide AÎČ1-42 dans le but de diminuer la prĂ©sence de petits oligomĂšres neurotoxiques. Les rĂ©sultats obtenus sont trĂšs prometteurs, nous avons rĂ©ussi Ă dĂ©velopper dâune part un pentapeptide capable dâinhiber totalement lâagrĂ©gation de AÎČ1-42, et dâautre part des pseudopentapeptides capables dâaccĂ©lĂ©rer son agrĂ©gation. Nous avons aussi dĂ©montrĂ© lâinfluence de lâatome de fluor sur la structuration dâun pentapeptide. Des Ă©tudes par RMN et DC sont en cours.ATP-sensitive potassium channels (KATP) play an important role in many cellular processes. The modulation of these channels by activating molecules may constitute very interesting pharmacological and medicinal applications. For this purpose, we have designed and synthesized new hybrid molecules cromakalim-diazoxide and diazoxide-amine/aminoacid. We also evaluated the relaxant activity of these compounds on aorta of rats. The obtained results do not show a significant relaxant effect. Studies on other tissues, including pancreatic cells and uterine muscle, are envisaged to explore the potency of these compounds and their possible tissue selectivity.Otherwise, Protein-protein interactions play a fundamental role in almost all cellular processes. They are strongly involved in the formation of the dimeric structure of HIV-1 protease and ÎČ amyloid peptide aggregation involved in Alzheimer's disease. Inhibition of these interactions would be a therapeutic advantage for the treatment of AIDS and Alzheimer's disease. We designed and synthesized on one hand, molecular tongs based on carbonylhydrazide oligohydrazid (Azatide) fragments and in the other hand, pentapeptide molecules with a central fluorinated and hydroxylated aminoacid. Finally, we tested the ability of molecular tongs to disrupt the terminal ÎČ sheet of the HIV-1 PR to inhibit its dimerization and thus its activity. We have also conducted a structure-activity relationship study and According to the results it seems that flexibility is detrimental to the inhibitory activity. We evaluated as well the ability of new fluorinated and hydroxylated peptidomimetics to accelerate or inhibit the aggregation of AÎČ1-42 peptide in order to reduce the presence of small toxic oligomers. The results are very promising that we succeeded in developing a pentapeptide able to completely inhibit the aggregation of AÎČ1-42, and in the other hand pseudopentapeptides able to accelerate its aggregation. We also demonstrated the influence of fluorine on the structure of a pentapeptides. Studies by NMR and DC are in progress
SynthÚse et évaluation pharmacologique de nouveaux peptides biomimétiques et de benzothiadiazines
ATP-sensitive potassium channels (KATP) play an important role in many cellular processes. The modulation of these channels by activating molecules may constitute very interesting pharmacological and medicinal applications. For this purpose, we have designed and synthesized new hybrid molecules cromakalim-diazoxide and diazoxide-amine/aminoacid. We also evaluated the relaxant activity of these compounds on aorta of rats. The obtained results do not show a significant relaxant effect. Studies on other tissues, including pancreatic cells and uterine muscle, are envisaged to explore the potency of these compounds and their possible tissue selectivity.Otherwise, Protein-protein interactions play a fundamental role in almost all cellular processes. They are strongly involved in the formation of the dimeric structure of HIV-1 protease and ÎČ amyloid peptide aggregation involved in Alzheimer's disease. Inhibition of these interactions would be a therapeutic advantage for the treatment of AIDS and Alzheimer's disease. We designed and synthesized on one hand, molecular tongs based on carbonylhydrazide oligohydrazid (Azatide) fragments and in the other hand, pentapeptide molecules with a central fluorinated and hydroxylated aminoacid. Finally, we tested the ability of molecular tongs to disrupt the terminal ÎČ sheet of the HIV-1 PR to inhibit its dimerization and thus its activity. We have also conducted a structure-activity relationship study and According to the results it seems that flexibility is detrimental to the inhibitory activity. We evaluated as well the ability of new fluorinated and hydroxylated peptidomimetics to accelerate or inhibit the aggregation of AÎČ1-42 peptide in order to reduce the presence of small toxic oligomers. The results are very promising that we succeeded in developing a pentapeptide able to completely inhibit the aggregation of AÎČ1-42, and in the other hand pseudopentapeptides able to accelerate its aggregation. We also demonstrated the influence of fluorine on the structure of a pentapeptides. Studies by NMR and DC are in progress.Les canaux potassiques sensibles Ă lâATP (KATP) jouent un rĂŽle primordial dans plusieurs processus cellulaires. La modulation de ces canaux par des molĂ©cules activatrices constituerait des applications pharmacologiques et mĂ©dicinales trĂšs intĂ©ressantes. Ă cet effet nous avons conçu et synthĂ©tisĂ© de nouvelles molĂ©cules hybrides cromakalim-diazoxide et diazoxide-amine/aminoacide. Nous avons Ă©galement, Ă©valuĂ© lâactivitĂ© myorelaxante de ces composĂ©s sur lâaorte de rates. Les rĂ©sultats obtenus ne montrent pas un effet myorelaxant significatif. Des Ă©tudes sur dâautres tissus, notamment les cellules ÎČ pancrĂ©atiques et le muscle utĂ©rin, sont envisagĂ©es afin dâexplorer une Ă©ventuelle sĂ©lectivitĂ© tissulaire. Par ailleurs, les interactions protĂ©ine-protĂ©ine jouent un rĂŽle fondamental dans presque tous les processus cellulaires. Elles sont fortement impliquĂ©es dans la formation de la structure dimĂ©rique de la protĂ©ase du VIH-1 et lâagrĂ©gation du peptide ÎČ amyloĂŻde impliquĂ©e dans la maladie dâAlzheimer. Lâinhibition de ces interactions serait donc dâun avantage thĂ©rapeutique pour le traitement du SIDA et de la maladie dâAlzheimer. Nous avons conçu et synthĂ©tisĂ© dâune part, des pinces molĂ©culaires Ă base de motifs carbonylhydrazides et oligohydrazides (Azatide), et dâautre part, des molĂ©cules pentapeptidiques avec un peudoaminoacide central alcoolfluorĂ©. Enfin, nous avons testĂ© la capacitĂ© des pinces molĂ©culaires Ă perturber le feuillet ÎČ terminal de la PR du VIH-1 afin d'inhiber sa dimĂ©risation et donc son activitĂ©. Nous avons rĂ©alisĂ© de mĂȘme une Ă©tude de relation structure-activitĂ© et dâaprĂšs lâensemble des rĂ©sultats obtenus, il semblerait que la flexibilitĂ© est dĂ©lĂ©tĂšre pour lâactivitĂ© inhibitrice. Nous avons Ă©galement Ă©valuĂ© la capacitĂ© des nouvelles molĂ©cules peptidomimĂ©tiques alcool fluorĂ©es Ă accĂ©lĂ©rer ou inhiber lâagrĂ©gation du peptide AÎČ1-42 dans le but de diminuer la prĂ©sence de petits oligomĂšres neurotoxiques. Les rĂ©sultats obtenus sont trĂšs prometteurs, nous avons rĂ©ussi Ă dĂ©velopper dâune part un pentapeptide capable dâinhiber totalement lâagrĂ©gation de AÎČ1-42, et dâautre part des pseudopentapeptides capables dâaccĂ©lĂ©rer son agrĂ©gation. Nous avons aussi dĂ©montrĂ© lâinfluence de lâatome de fluor sur la structuration dâun pentapeptide. Des Ă©tudes par RMN et DC sont en cours
SynthÚse et évaluation pharmacologique de nouveaux peptides biomimétiques et de benzothiadiazines
Les canaux potassiques sensibles Ă l ATP (KATP) jouent un rĂŽle primordial dans plusieurs processus cellulaires. La modulation de ces canaux par des molĂ©cules activatrices constituerait des applications pharmacologiques et mĂ©dicinales trĂšs intĂ©ressantes. Ă cet effet nous avons conçu et synthĂ©tisĂ© de nouvelles molĂ©cules hybrides cromakalim-diazoxide et diazoxide-amine/aminoacide. Nous avons Ă©galement, Ă©valuĂ© l activitĂ© myorelaxante de ces composĂ©s sur l aorte de rates. Les rĂ©sultats obtenus ne montrent pas un effet myorelaxant significatif. Des Ă©tudes sur d autres tissus, notamment les cellules b pancrĂ©atiques et le muscle utĂ©rin, sont envisagĂ©es afin d explorer une Ă©ventuelle sĂ©lectivitĂ© tissulaire. Par ailleurs, les interactions protĂ©ine-protĂ©ine jouent un rĂŽle fondamental dans presque tous les processus cellulaires. Elles sont fortement impliquĂ©es dans la formation de la structure dimĂ©rique de la protĂ©ase du VIH-1 et l agrĂ©gation du peptide b amyloĂŻde impliquĂ©e dans la maladie d Alzheimer. L inhibition de ces interactions serait donc d un avantage thĂ©rapeutique pour le traitement du SIDA et de la maladie d Alzheimer. Nous avons conçu et synthĂ©tisĂ© d une part, des pinces molĂ©culaires Ă base de motifs carbonylhydrazides et oligohydrazides (Azatide), et d autre part, des molĂ©cules pentapeptidiques avec un peudoaminoacide central alcoolfluorĂ©. Enfin, nous avons testĂ© la capacitĂ© des pinces molĂ©culaires Ă perturber le feuillet b terminal de la PR du VIH-1 afin d'inhiber sa dimĂ©risation et donc son activitĂ©. Nous avons rĂ©alisĂ© de mĂȘme une Ă©tude de relation structure-activitĂ© et d aprĂšs l ensemble des rĂ©sultats obtenus, il semblerait que la flexibilitĂ© est dĂ©lĂ©tĂšre pour l activitĂ© inhibitrice. Nous avons Ă©galement Ă©valuĂ© la capacitĂ© des nouvelles molĂ©cules peptidomimĂ©tiques alcool fluorĂ©es Ă accĂ©lĂ©rer ou inhiber l agrĂ©gation du peptide Ab1-42 dans le but de diminuer la prĂ©sence de petits oligomĂšres neurotoxiques. Les rĂ©sultats obtenus sont trĂšs prometteurs, nous avons rĂ©ussi Ă dĂ©velopper d une part un pentapeptide capable d inhiber totalement l agrĂ©gation de Ab1-42, et d autre part des pseudopentapeptides capables d accĂ©lĂ©rer son agrĂ©gation. Nous avons aussi dĂ©montrĂ© l influence de l atome de fluor sur la structuration d un pentapeptide. Des Ă©tudes par RMN et DC sont en cours.ATP-sensitive potassium channels (KATP) play an important role in many cellular processes. The modulation of these channels by activating molecules may constitute very interesting pharmacological and medicinal applications. For this purpose, we have designed and synthesized new hybrid molecules cromakalim-diazoxide and diazoxide-amine/aminoacid. We also evaluated the relaxant activity of these compounds on aorta of rats. The obtained results do not show a significant relaxant effect. Studies on other tissues, including pancreatic cells and uterine muscle, are envisaged to explore the potency of these compounds and their possible tissue selectivity.Otherwise, Protein-protein interactions play a fundamental role in almost all cellular processes. They are strongly involved in the formation of the dimeric structure of HIV-1 protease and b amyloid peptide aggregation involved in Alzheimer's disease. Inhibition of these interactions would be a therapeutic advantage for the treatment of AIDS and Alzheimer's disease. We designed and synthesized on one hand, molecular tongs based on carbonylhydrazide oligohydrazid (Azatide) fragments and in the other hand, pentapeptide molecules with a central fluorinated and hydroxylated aminoacid. Finally, we tested the ability of molecular tongs to disrupt the terminal b sheet of the HIV-1 PR to inhibit its dimerization and thus its activity. We have also conducted a structure-activity relationship study and According to the results it seems that flexibility is detrimental to the inhibitory activity. We evaluated as well the ability of new fluorinated and hydroxylated peptidomimetics to accelerate or inhibit the aggregation of Ab1-42 peptide in order to reduce the presence of small toxic oligomers. The results are very promising that we succeeded in developing a pentapeptide able to completely inhibit the aggregation of Ab1-42, and in the other hand pseudopentapeptides able to accelerate its aggregation. We also demonstrated the influence of fluorine on the structure of a pentapeptides. Studies by NMR and DC are in progress.PARIS11-SCD-Bib. Ă©lectronique (914719901) / SudocSudocFranceF
Supramolecular Nanostructures Based on Perylene Diimide Bioconjugates: From Self-Assembly to Applications
Self-assembling π-conjugated systems constitute efficient building blocks for the construction of supramolecular structures with tailored functional properties. In this context, perylene diimide (PDI) has attracted attention owing to its chemical robustness, thermal and photo-stability, and outstanding optical and electronic properties. Recently, the conjugation of PDI derivatives to biological molecules, including oligonucleotides and peptides, has opened new avenues for the design of nanoassemblies with unique structures and functionalities. In the present review, we offer a comprehensive summary of supramolecular bio-assemblies based on PDI. After briefly presenting the physicochemical, structural, and optical properties of PDI derivatives, we discuss the synthesis, self-assembly, and applications of PDI bioconjugates
Synthesis and pharmacological activity of N-(2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-4H-1,2,4-benzothiadiazine-3-carboxamides 1,1-dioxides on rat uterus, rat aorta and rat pancreatic ÎČ-cells.
N-(2,2-Dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-4H-1,2,4-benzothiadiazine-3-carboxamides 1,1-dioxides were prepared and evaluated on rat uterus, rat aortic rings and rat pancreatic ÎČ-cells. Pharmacological studies conducted on rat uterus indicated that several of these original hybrid compounds displayed a strong myorelaxant activity. The most active compounds hold a bromine atom at the 6-position of the dihydrobenzopyran ring. Moreover, the compounds failed to display a marked inhibitory effect on insulin secretion and vascular myogenic activity. These features suggest that the 6-bromo compounds could be relatively selective towards the uterine smooth muscle.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe
The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic ÎČ-strands
Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF3-threonine and (2S,3S)-L-CF3-threonine were prepared. The capacity of (2S,3S)- and (2S,3R)-CF3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF3-threonine containing pentapeptides are more prone to mimic ÎČ-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated ÎČ-strand mimics are able to disrupt proteinâprotein interactions involving ÎČ-sheet structures is provided. The CF3-threonine containing pentapeptides interact with the amyloid peptide AÎČ1-42 in order to reduce the proteinâprotein interactions mediating its aggregation process
Carbonylhydrazide-Based Molecular Tongs Inhibit Wild-Type and Mutated HIV-1 Protease Dimerization
International audienceWe have designed and synthesized new molecular tongs based on a rigid naphthalene scaffold and evaluated their antidimer activity on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide (azatide) fragments into their peptidomimetic arms to reduce hydrophobicity and increase metabolic stability. These fragments are designed to disrupt the protein-protein interactions by reproducing the hydrogen bond pattern found in the antiparallel beta-sheet formed between the N- and C-ends of the two monomers in the native PR. Kinetic analyses and fluorescent probe binding studies showed that several molecular tongs can inhibit PR dimerization. The best nonpeptidic molecular tongs to date were obtained with an inhibition constant K-id of 50 nM for PR and 80 nM for the multimutated protease ANAM-11. The PR inhibition was selective, the aspartic proteases renin and pepsin were not inhibited
Carbonylhydrazide-Based Molecular Tongs Inhibit Wild-Type and Mutated HIVâ1 Protease Dimerization
We have designed and synthesized new molecular tongs
based on a
rigid naphthalene scaffold and evaluated their antidimer activity
on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide
(azatide) fragments into their peptidomimetic arms to reduce hydrophobicity
and increase metabolic stability. These fragments are designed to
disrupt the proteinâprotein interactions by reproducing the
hydrogen bond pattern found in the antiparallel ÎČ-sheet formed
between the <i>N</i>- and <i>C</i>-ends of the
two monomers in the native PR. Kinetic analyses and fluorescent probe
binding studies showed that several molecular tongs can inhibit PR
dimerization. The best nonpeptidic molecular tongs to date were obtained
with an inhibition constant <i>K</i><sub>id</sub> of 50
nM for PR and 80 nM for the multimutated protease ANAM-11. The PR
inhibition was selective, the aspartic proteases renin and pepsin
were not inhibited