Antiviral drug design, dynthesis and biological evaluation for treatment of Hepatitis C virus

Hepatitis C virus is an infectious disease affecting millions of people worldwide and causing chronic liver disease. The current standard of care is not only long but causes numerous side effects. Due to incomplete virological response and poor tolerability, only 50% of the patients are cured, with variability by genotype. Despite the development of non-enzymatic viral protein inhibitors, new therapies target mainly enzymes responsible for viral replication or translation. Being commonly used for antiviral and anticancer therapy, nucleosides analogues have played an important role as anti-HCV agents. Despite their potency and selectivity, nucleoside analogues appear to be poor substrates for metabolic enzymes. In particular, the first essential phosphorylation step is often rate-limiting thus, resulting in poor bioactivation to the active triphosphate form. Hence, monophosphate prodrug strategies have been applied to efficiently deliver intracellularly the key monophosphate derivatives. Such strategies have been successfully used for anti-HCV therapy and the phosphoramidate ProTide INX-08189, discovered in our lab, is one such example. Aiming at developing back-up molecules of INX-08189, we report in the present work, the synthetic strategies to obtain several modified β-2’-C-methyl-6-O-methyl guanosine and other modified β-2’-C-methyl purine nucleoside analogues. The phosphoramidate ProTide approach and the phosphorodiamidate approach were applied to these modified nucleosides. In-vitro, and sometimes in-vivo evaluation against HCV replication is reported, and the mechanism of bioactivation to their corresponding monophosphate species is discussed. Enzymatic experiments using carboxypeptidase Y and Huh-7 cell lysates were carried out to investigate the release of the monophosphate forms. We also investigated the hydrolysis of the 6-O-methyl group at the nucleoside level with adenosine deaminase enzyme, and at the monophosphate level using molecular docking in adenosine deaminase like protein-1. Eventually, the intracellular putative mechanism of activation of the ProTides was studied using molecular modeling with cathepsin A enzyme and human Hint-1 phosphoramidase

Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups

he design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups

Thermally triggerable, anchoring block copolymers for use in aqueous inkjet printing

Towards the goal of shifting from toxic organic solvents to aqueous-based formulations in commercial inkjet printing, a series of well-defined poly[(2-hydroxyethyl acrylate-stat-N-hydroxymethyl acrylamide)-block-propyl methacrylate], P[(HEA-st-HMAA)-b-PMA], amphiphilic block copolymers with varying degrees of polymerization and comonomer compositions were synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization. Optimized RAFT polymerization conditions were found to allow larger batch synthesis (>20 g scale) without compromise over molecular design control (molecular mass, hydrophobic/hydrophilic balance, dispersity, etc.). The copolymers were subsequently investigated for their crosslinking and adhesive properties, as well as jetting performance, to determine their suitability for use in aqueous ink formulations. Crosslinking was found to occur much faster for copolymers containing more of the crosslinkable HMAA monomer units and at higher molecular masses, allowing control over the required post-deposition processing time. The amphiphilic block copolymers synthesized herein demonstrate enhanced adhesive properties compared to a selection of commercial inks whilst also achieving high print quality and performance for use in aqueous continuous inkjet (CIJ) printing, which is a key step towards greener processes in the packaging industries, where printing onto hydrophobic substrates is needed

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Selective therapy with minor groove binders

Over the past five years, the University of Strathclyde has developed extremely potent anti-bacterial molecules known as minor groove binding agents (MGB) which intrinsic helicity allows binding to the minor groove of DNA. These molecules were effective in vivo, non-toxic and showed activity and selectivity against Gram positive bacteria. Whilst such selectivity is an advantage, an extension of activity of such agents towards Gram negative organisms and eventually targeting cancer cells would be valuable. Since the biological properties of such minor groove bonders are related to the chemical feature, this aim could be achieved by modifying the structure of the tail group only. The MPhil project involved the synthesis of a small number of selected minor groove binders differing in their tail groups (Boc protected, OAc protected, guanidine, cyano alkene, nitro alkene) but bearing the same fluorescent head group ((E)-4-(3-methoxystyryl)benzyl). The yield of the coupling reaction between the head group and the pyrrole-pyrrole core linked with a protected tail group (Boc or OAc) was improved up to two- to five- fold, using propane phosphonic acid anhydride as a mild reagent. These MGBs were then evaluated for anti-bacterial and anti-cancer drug activity in screens available at the Strathclyde Institute of Pharmaceutical and Biological Sciences (SIPBS). They were tested against Gram negative E. coli, against Gram positive Staph. aureus and against the fibroblast hamster cell line V79, in order to evaluate respectively their anti-bacterial activity and their toxicity. The penetration of these synthesized molecules into bacteria and cells was observed under microscopy in order to assess the structural features that could lead to a potential anti-bacterial and/or anti-cancer molecule if nuclear permeation occurs. Almost all MGBs tested permeate into Gram positive bacteria, but not all of them showed an anti-bacterial activity. These results were consistent with earlier experiments. However permeation in Gram negative bacteria was observed for the first time in these kind of MGB, but only one molecule appeared to be toxic towards this family of Gram negative bacteria above 20μg/mL. Furthermore, tested MGBs showed permeation into V79 mammalian cells with or without reaching the nucleus, and only one molecule developed significant toxicity towards the V79 cell line, thus giving an idea of which molecule could potentially bind to DNA and become a potential anti-cancer drug.Over the past five years, the University of Strathclyde has developed extremely potent anti-bacterial molecules known as minor groove binding agents (MGB) which intrinsic helicity allows binding to the minor groove of DNA. These molecules were effective in vivo, non-toxic and showed activity and selectivity against Gram positive bacteria. Whilst such selectivity is an advantage, an extension of activity of such agents towards Gram negative organisms and eventually targeting cancer cells would be valuable. Since the biological properties of such minor groove bonders are related to the chemical feature, this aim could be achieved by modifying the structure of the tail group only. The MPhil project involved the synthesis of a small number of selected minor groove binders differing in their tail groups (Boc protected, OAc protected, guanidine, cyano alkene, nitro alkene) but bearing the same fluorescent head group ((E)-4-(3-methoxystyryl)benzyl). The yield of the coupling reaction between the head group and the pyrrole-pyrrole core linked with a protected tail group (Boc or OAc) was improved up to two- to five- fold, using propane phosphonic acid anhydride as a mild reagent. These MGBs were then evaluated for anti-bacterial and anti-cancer drug activity in screens available at the Strathclyde Institute of Pharmaceutical and Biological Sciences (SIPBS). They were tested against Gram negative E. coli, against Gram positive Staph. aureus and against the fibroblast hamster cell line V79, in order to evaluate respectively their anti-bacterial activity and their toxicity. The penetration of these synthesized molecules into bacteria and cells was observed under microscopy in order to assess the structural features that could lead to a potential anti-bacterial and/or anti-cancer molecule if nuclear permeation occurs. Almost all MGBs tested permeate into Gram positive bacteria, but not all of them showed an anti-bacterial activity. These results were consistent with earlier experiments. However permeation in Gram negative bacteria was observed for the first time in these kind of MGB, but only one molecule appeared to be toxic towards this family of Gram negative bacteria above 20μg/mL. Furthermore, tested MGBs showed permeation into V79 mammalian cells with or without reaching the nucleus, and only one molecule developed significant toxicity towards the V79 cell line, thus giving an idea of which molecule could potentially bind to DNA and become a potential anti-cancer drug

“Rehab for all!” Is it too early in pulmonary arterial hypertension?

International audienc

Un siècle de journalisme culturel en Normandie et dans d'autres provinces

En onze contributions, ce recueil analyse les pratiques du journalisme culturel dans la province française, au cours du siècle qui suit la création en 1785 du Journal de Rouen. S'inscrivant dans une tradition encyclopédique et dominée par une activité théâtrale souvent intense, la chronique de l'actualité culturelle cherche à promouvoir, à travers des auteurs, des œuvres ou des événements, la production intellectuelle locale. Mais elle constitue aussi, sans spécialisation rédactionnelle affirmée et avant la loi de 1881 sur la liberté de la presse, un moyen d'échapper aux tentatives du pouvoir d'instrumentaliser la culture et de faire passer, malgré la censure, des idées nouvelles et une critique sociale ou politique sous couvert de gazette des spectacles ou d'articles d'érudition

When the West Meets the South on Screen

Like the classic movies on the Far West, the quintessential film narratives of the Deep South have greatly impacted the popular understanding of American history and American values. While the canonized Western has relentlessly foregrounded the idea of individual freedom and the conquest of the wilderness, the more elusive and controversial Southern genre bears the persistent ideological traces of slavery and segregation. However, this Revue LISA/LISA e-journal issue “When the West/ern meets the South/ern” explores the jarring and often unexpected connections between the two basically distinct generic categories, well before the 2012 release of Django unchained, Quentin Tarantino’s provocatively Westernized Southern (or Southernized Western). Numerous earlier films were already engaged in a play with the representational codes of the West and the South in cinema and literature. When the Western and the Southern cross and blend, the resultant “genre trouble” generates a more complex image of America, challenging its grand narratives and myths. À l’instar des films classiques sur le Far West, les récits cinématographiques sur le Sud profond (« the Deep South ») ont considérablement influencé la compréhension populaire de l’histoire et des valeurs américaines. Alors que l’Ouest canonique a inlassablement mis en avant l’idée de la liberté individuelle et celle de la conquête de la wilderness, le genre Southern, plus controversé et plus difficile à cerner, continue à porter les stigmates de l’esclavage et de la ségrégation. Pourtant, ce numéro spécial de la Revue LISA/LISA e-journal intitulé « Quand l’Ouest rencontre le Sud à l’écran » explore les rapprochements, souvent inattendus et stimulants, entre deux catégories génériques a priori distinctes, bien avant Django Unchained de Quentin Tarantino (2012), un Southern westernien (ou un Western southernien). De nombreux films antérieurs jouaient déjà avec les codes de représentations de l’Ouest et du Sud à l’écran et dans la littérature. Lorsque le Western et le Southern se croisent et s’hybrident, le « trouble dans le genre » qui en résulte génère une image plus complexe de l’Amérique tout en interrogeant ses grands récits et mythes