Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Sharon Wein is active.

Publication


Featured researches published by Sharon Wein.


Journal of Clinical Microbiology | 2010

Reliability of Antimalarial Sensitivity Tests Depends on Drug Mechanisms of Action

Sharon Wein; Marjorie Maynadier; Christophe Tran Van Ba; Rachel Cerdan; Suzanne Peyrottes; Laurent Fraisse; Henri Vial

ABSTRACT In vitro antimalarial activity tests play a pivotal role in malaria drug research or for monitoring drug resistance in field isolates. We applied two isotopic tests, two enzyme-linked immunosorbent assays (ELISA) and the SYBR green I fluorescence-based assay, to test artesunate and chloroquine, the metabolic inhibitors atovaquone and pyrimethamine, our fast-acting choline analog T3/SAR97276, and doxycycline, which has a delayed death profile. Isotopic tests based on hypoxanthine and ethanolamine incorporation are the most reliable tests provided when they are applied after one full 48-h parasite cycle. The SYBR green assay, which measures the DNA content, usually requires 72 h of incubation to obtain reliable results. When delayed death is suspected, specific protocols are required with increasing incubation times up to 96 h. In contrast, both ELISA tests used (pLDH and HRP2) appear to be problematic, leading to disappointing and even erroneous results for molecules that do not share an artesunatelike profile. The reliability of these tests is linked to the mode of action of the drug, and the conditions required to get informative results are hard to predict. Our results suggest some minimal conditions to apply these tests that should give rise to a standard 50% inhibitory concentration, regardless of the mechanism of action of the compounds, and highlight that the most commonly used in vitro antimalarial activity tests do not have the same potential. Some of them might not detect the antimalarial potential of new classes of compounds with innovative modes of action, which subsequently could become promising new antimalarial drugs.


Journal of Lipid Research | 2010

Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways.

Sandrine Déchamps; Marjorie Maynadier; Sharon Wein; Laila Gannoun-Zaki; Eric Maréchal; Henri Vial

Malaria, a disease affecting humans and other animals, is caused by a protist of the genus Plasmodium. At the intraerythrocytic stage, the parasite synthesizes a high amount of phospholipids through a bewildering number of pathways. In the human Plasmodium falciparum species, a plant-like pathway that relies on serine decarboxylase and phosphoethanolamine N-methyltransferase activities diverts host serine to provide additional phosphatidylcholine and phosphatidylethanolamine to the parasite. This feature of parasitic dependence toward its host was investigated in other Plasmodium species. In silico analyses led to the identification of phosphoethanolamine N-methyltransferase gene orthologs in primate and bird parasite genomes. However, the gene was not detected in the rodent P. berghei, P. yoelii, and P. chabaudi species. Biochemical experiments with labeled choline, ethanolamine, and serine showed marked differences in biosynthetic pathways when comparing rodent P. berghei and P. vinckei, and human P. falciparum species. Notably, in both rodent parasites, ethanolamine and serine were not significantly incorporated into phosphatidylcholine, indicating the absence of phosphoethanolamine N-methyltransferase activity. To our knowledge, this is the first study to highlight a crucial difference in phospholipid metabolism between Plasmodium species. The findings should facilitate efforts to develop more rational approaches to identify and evaluate new targets for antimalarial therapy.


Journal of Medicinal Chemistry | 2012

Disulfide Prodrugs of Albitiazolium (T3/SAR97276): Synthesis and Biological Activities

Sergio A. Caldarelli; Matthieu Hamel; Jean‐Frédéric Duckert; Mahama Ouattara; Michèle Calas; Marjorie Maynadier; Sharon Wein; Christian Périgaud; Alain Pellet; Henri Vial; Suzanne Peyrottes

We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.


Antimicrobial Agents and Chemotherapy | 2006

Potent Antihematozoan Activity of Novel Bisthiazolium Drug T16: Evidence for Inhibition of Phosphatidylcholine Metabolism in Erythrocytes Infected with Babesia and Plasmodium spp.

Eric Richier; Giancarlo A. Biagini; Sharon Wein; Frederic Boudou; Patrick G. Bray; Steve A. Ward; Eric Precigout; Michèle Calas; Jean-François Dubremetz; Henri Vial

ABSTRACT A leading bisthiazolium drug, T16, designed to mimic choline, was shown to exert potent antibabesial activity, with 50% inhibitory concentrations of 28 and 7 nM against Babesia divergens and B. canis, respectively. T16 accumulated inside Babesia-infected erythrocytes (cellular accumulation ratio, >60) by a saturable process with an apparent Km of 0.65 μM. Subcellular fractionation of Babesia parasites revealed the accumulation of T16 into a low-density fraction, while in malaria-infected erythrocytes a significant fraction of the drug was associated with heme malaria pigment. T16 exerts an early and specific inhibition of the de novo biosynthesis of phosphatidylcholine both in B. divergens- and Plasmodium falciparum-infected erythrocytes. Choline accumulation into isolated Babesia parasites was highly sensitive to inhibition by T16. These data are consistent with the hypothesis that bisthiazolium drugs target the de novo phosphatidylcholine biosynthesis of intraerythrocytic hematozoan parasites. In malaria parasites, which generate ferriprotoporphyrin IX during hemoglobin digestion, T16 binding to heme may enhance the accumulation and activity of the drug. The selectivity of accumulation and potent activity of this class of drug into parasite-infected erythrocytes offers unique advantages over more traditional antihematozoan drugs.


Current Pharmaceutical Design | 2012

Choline analogues in malaria chemotherapy.

Suzanne Peyrottes; Sergio A. Caldarelli; Sharon Wein; Christian Périgaud; Alain Pellet; Henri Vial

Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches.


Antimicrobial Agents and Chemotherapy | 2005

Pharmacological Properties of a New Antimalarial Bisthiazolium Salt, T3, and a Corresponding Prodrug, TE3

Olivier Nicolas; Delphine Margout; Nicolas Taudon; Sharon Wein; Michèle Calas; Henri Vial; Françoise Bressolle

ABSTRACT A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).


Bioorganic & Medicinal Chemistry Letters | 2009

Design and synthesis of amidoxime derivatives for orally potent C-alkylamidine-based antimalarial agents

Mahama Ouattara; Sharon Wein; Séverine Denoyelle; Stéphanie Ortial; Thierry Durand; Roger Escale; Henri Vial; Yen Vo-Hoang

Within the frame of the design of prodrug candidates to deliver a C-alkylamidine antimalarial agent, we showed that specific O-substitutions were needed on the alkylamidoxime structure. Among the newly synthesized molecules, bis-oxadiazolone and bis-O-methylsulfonylamidoxime derivatives induced a complete clearance of parasitemia in mice after oral administration.


Bioorganic & Medicinal Chemistry Letters | 2010

Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.

Sergio A. Caldarelli; Michel Boisbrun; Karine Alarcon; Abdallah Hamze; Mahama Ouattara; Xavier J. Salom-Roig; Marjorie Maynadier; Sharon Wein; Suzanne Peyrottes; Alain Pellet; Michèle Calas; Henri Vial

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.


Journal of Medicinal Chemistry | 2013

New bis-thiazolium analogues as potential antimalarial agents: design, synthesis, and biological evaluation.

Sergio A. Caldarelli; Siham El Fangour; Sharon Wein; Christophe Tran Van Ba; Christian Périgaud; Alain Pellet; Henri Vial; Suzanne Peyrottes

Bis-thiazolium salts are able to inhibit phosphatidylcholine biosynthesis in Plasmodium and to block parasite proliferation in the low nanomolar range. However, due to their physicochemical properties (i.e., permanent cationic charges, the flexibility, and lipophilic character of the alkyl chain), the oral bioavailability of these compounds is low. New series of bis-thiazolium-based drugs have been designed to overcome this drawback. They feature linker rigidification via the introduction of aromatic rings and/or a decrease in the overall lipophilicity through the introduction of heteroatoms. On the basis of the structure-activity relationships, a few of the promising compounds (9, 10, and 11) were found to exhibit potent antimalarial in vitro and in vivo activities (EC(50) < 10 nM and ED(50) ip < 0.7 mg/kg).


Bioorganic & Medicinal Chemistry Letters | 2009

N-substituted bis-C-alkyloxadiazolones as dual effectors: efficient intermediates to amidoximes or amidines and prodrug candidates of potent antimalarials.

Mélissa Degardin; Sharon Wein; Thierry Durand; Roger Escale; Henry Vial; Yen Vo-Hoang

A convenient route to N-substituted bis-C-alkylamidines possessing antiplasmodial activity and their oxadiazolone and amidoxime prodrug candidates, is described. These three families of compounds were available after a key N-alkylation step of the parent oxadiazolone 1a. Testing of the three compound classes in vitro and in vivo is also presented.

Collaboration


Dive into the Sharon Wein's collaboration.

Top Co-Authors

Avatar

Henri Vial

University of Montpellier

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Michèle Calas

University of Montpellier

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Roger Escale

University of Montpellier

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Thierry Durand

University of Montpellier

View shared research outputs
Top Co-Authors

Avatar

Yen Vo-Hoang

University of Montpellier

View shared research outputs
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge