Serine protease inhibitors to treat inflammation: a patent review (2011-2016)

International audienceIntroduction: Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation.Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016.Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammatory arthritis. Several serine proteases were selected for their contribution to inflammatory diseases and significant efforts that are spread to develop inhibitors. Strategies developed for inhibitor identification consist on either peptide-based inhibitor derived from endogenous protein inhibitors or small-organic molecules. It is also worth noting that among the recent patents on serine protease inhibitors related to inflammation a significant number are related to retinal vascular dysfunction and skin diseases

The dermaseptin superfamily: A gene-based combinatorial library of antimicrobial peptides

AbstractSkin secretions of hylid frogs show amazing levels of interspecific and intraspecific diversity and are comprised of a cocktail of genetically-related, but markedly diverse antimicrobial peptides that are grouped into a superfamily, termed the dermaseptins, comprising several families: dermaseptins (sensu stricto), phylloseptins, plasticins, dermatoxins, phylloxins, hyposins, caerins, and aureins. Dermaseptin gene superfamily evolution is characterized by repeated gene duplications and focal hypermutations of the mature peptide coding sequence, followed by positive (diversifying) selection. We review here molecular mechanisms leading to these vast combinatorial peptide libraries, and structural and functional properties of antimicrobial peptides of the dermaseptin and plasticin families, as well as those of dermaseptin S9, an amyloidogenic peptide with antimicrobial and chemoattractant activities

REPLIEMENTS D'ADN (VARIATIONS AUTOUR D'UN SITE DE COUPURE PREFERENTIEL DE LA TOPOISOMERASE II)

LA TOPOISOMERASE II MODULE LES ETATS TOPOLOGIQUES DE L'ADN. ELLE RECONNAIT ET CLIVE NOTAMMENT LES STRUCTURES EN EPINGLES A CHEVEUX. UN SITE PREFERENTIEL DE COUPURE EN PRESENCE D'AGENTS ANTITUMORAUX A ETE IDENTIFIE AU SEIN DE L'ADN DE PBR322. IL CONTIENT UN SEGMENT DE 19 PAIRES DE BASES DE SYMETRIE INVERSEE-REPETEE : W D (5AGCTTATC ATC GATAAGCT 3). C D (5AGCTTATC GAT GATAAGCT 3). L'ETUDE RMN A MONTRE QUE CHACUN DES BRINS PRIS SEPAREMENT ADOPTAIT UNE STRUCTURE EN EPINGLES A CHEVEUX AVEC UNE TIGE A HUIT/DIX PAIRES DE BASES ET UNE BOUCLE A TROIS/UN RESIDU. AU COURS DE CE TRAVAIL DE THESE NOUS AVONS ANALYSE L'IMPACT DE CERTAINS PARAMETRES STRUCTURAUX SUR LA STABILITE ET LA CONFORMATION DES BOUCLES A L'AIDE DES SPECTROSCOPIES UV, DE DICHROISME CIRCULAIRE, ET DE RMN UTILISANT COMME MODELE SIMPLE BRIN D'ADN D (5AGCTTATC XXX GATAAGCT 3), OU XXX = GAC, CAG, AT(L)C (THYMIDINE CENTRALE DE CONFIGURATION L). NOUS AVONS EVALUE L'EQUILIBRE CRITIQUE (DEPENDANT DE LA CONCENTRATION EN OLIGONUCLEOTIDES) ENTRE LA FORME EN EPINGLES A CHEVEUX ET LA FORME EN DUPLEX PAR LA MESURE DES COEFFICIENTS DE DIFFUSION TRANSLATIONNELLE. CEUX-CI INDIQUENT QU'AUX CONCENTRATIONS DE LA RMN (MM) LES ADNS CONTENANT GAC ET AT(L)C SE REPLIENT EN EPINGLES A CHEVEUX. TANDIS QUE L'OLIGONUCLEOTIDE CAG FORME UN DUPLEX AVEC UN MESAPPARIEMMENT A.A EN SON CENTRE. LA MODELISATION MONTRE QUE : (1) GAC ADOPTE UNE BOUCLE A RESIDU UNIQUE FERMEE PAR UNE PAIRE DE BASES WATSON-CRICK DISTORDUE TOTALEMENT ATYPIQUE LONGTEMPS CONSIDEREE COMME STERIQUEMENT IMPOSSIBLE ; (2) AT(L)C EST HAUTEMENT FLEXIBLE CE QUI S'EXPLIQUE PAR L'ABOLITION DU MESAPPARIEMENT A.C CARACTERISANT ATC. UNE SIMULATION DE DYNAMIQUE MOLECULAIRE DE 5 NS EN EAU ET IONS EXPLICITES SUR LE DUPLEX CAG A REVELE UNE DISSYMETRIE DE MOUVEMENTS AUTOUR DU MESAPPARIEMENT A.A CENTRAL MAIS DANS CE CAS PARTICULIER D'AUTRES SIMULATIONS SONT NECESSAIRES POUR CONFIRMER CETTE PROPRIETE.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Les plasticines, peptides antibactériens de la peau de grenouille (versatilité fonctionnelle, adaptabilité des structures et des interactions membranaires)

La famille des plasticines se compose de peptides antibactériens issus de la peau de grenouilles arboricoles d Amérique du Sud. Ces peptides se distinguent par une séquence riche en glycine et en leucine et par la présence de motifs GXXXG, connus pour favoriser les interactions entre hélices transmembranaires. Leur plasticité structurale permet peut expliquer les subtiles différences de propriétés biologiques ainsi que la versatilité fonctionnelle de ces peptides. En conséquence, pour mieux comprendre les mécanismes d actions de ces peptides, trois axes ont été développés, (1) études des activités biologiques et multifonctionnalité des plasticines, (2) évaluation des modes d interactions et des perturbations membranaires et (3) études structurales et propriétés auto-associatives. Les différents résultats accumulés au cours cette thèse donnent un aperçu de la diversité des mécanismes aboutissant à une activité biologique sur la membrane d une cellule cible.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Staudinger Condensation for the Preparation of Thiohydantoins

International audienceAn efficient one-pot, two-step sequence starting from azide derivatives is described: first, formation of iminophosphoranes (Staudinger reaction) and condensation with carbon disulfide to form nonisolated isothiocyanates; then, condensation with alpha-amino esters to provide new N-3-substituted 2-thiohydantoins

Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

International audienceAtherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology is characterized by chronic inflammation, oxidative stress, gradual accumulation of low-density lipoproteins (LDL) particles and fibrous elements in focal areas of large and medium arteries. These fibrofatty lesions in the artery wall become progressively unstable and thrombogenic leading to heart attack, stroke or other severe heart ischemic syndromes. Elevated blood levels of LDL are major triggering events for atherosclerosis. A cascade of molecular and cellular events results in the atherosclerotic plaque formation, evolution, and rupture. Moreover, the senescence of multiple cell types present in the vasculature were reported to contribute to atherosclerotic plaque progression and destabilization. Classical therapeutic interventions consist of lipid-lowering drugs, anti-inflammatory and life style dispositions. Moreover, targeting oxidative stress by developing innovative antioxidant agents or boosting antioxidant systems is also a well-established strategy. Accumulation of senescent cells (SC) is also another important feature of atherosclerosis and was detected in various models. Hence, targeting SCs appears as an emerging therapeutic option, since senolytic agents favorably disturb atherosclerotic plaques. In this review, we propose a survey of the impact of inflammation, oxidative stress, and senescence in atherosclerosis; and the emerging therapeutic options, including thioredoxin-based approaches such as anti-oxidant, anti-inflammatory, and anti-atherogenic strategy with promising potential of senomodulation

Inhibitors of kallikrein-related peptidases: An overview

International audienceKallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition

The micro-distribution of carbonaceous matter in the Murchison meteorite as investigated by Raman imaging

The carbonaceous Murchison chondrite is one of the most studied meteorites. It is considered to be an astrobiology standard for detection of extraterrestrial organic matter. Considerable work has been done to resolve the elemental composition of this meteorite. Raman spectroscopy is a very suitable technique for non-destructive rapid in situ analyses to establish the spatial distribution of carbonaceous matter. This report demonstrates that Raman cartography at a resolution of 1 ?m2 can be performed. Two-dimensional distribution of graphitised carbon, amorphous carbonaceous matter and minerals were obtained on 100 ?m2 maps. Maps of the surface of native stones and of a powdered sample are compared. Graphitic and amorphous carbonaceous domains are found to be highly overlapping in all tested areas at the surface of the meteorite and in its interior as well. Pyroxene, olivine and iron oxide grains are embedded into this mixed carbonaceous material. The results show that every mineral grain with a size of less than a few ?m2 is encased in a thin carbonaceous matrix, which accounts for only 2.5 wt.%. This interstitial matter sticks together isolated mineral crystallites or concretions, including only very few individualized graphitised grains. Grinding separates the mineral particles but most of them retain their carbonaceous coating. This Raman study complements recent findings deduced from other spatial analyses performed by microprobe laser-desorption laser-ionisation mass spectrometry (?L2MS), transmission electron microscopy (TEM) and scanning transmission X-ray microscopy (STXM)

Synthesis and study of (R)- and (S)-β-hydroxyphosphonate acyclonucleosides as structural analogues of (S)-HPMPC (cidofovir).

International audienceA synthetic pathway to new acyclonucleoside phosphonates, designed as analogues of cidofovir, is described. The reduction of a β-ketophosphonate intermediate, readily available from the nucleobase and benzylacrylate, afforded an enantiomeric mixture of (R)- and (S)-β-hydroxyphosphonate derivatives which was resolved. The assignment of the absolute configuration was proposed on the basis of NMR studies. The influence of this modification, the presence of the hydroxyl group and chirality on the β-position related to the phosphorus atom, on antiviral activity against a broad variety of DNA and RNA viruses and also on the capacity to be recognized as substrates by human NMP kinases was investigated

Borononucleotides as Substrates/Binders for Human NMP Kinases: Enzymatic and Spectroscopic Evaluation

International audienc