Search results for " Bruce"
showing 10 items of 46 documents
Identification of Plakortide E from the Caribbean Sponge Plakortis halichondroides as a Trypanocidal Protease Inhibitor using Bioactivity-Guided Frac…
2014
In this paper, we report new protease inhibitory activity of plakortide E towards cathepsins and cathepsin-like parasitic proteases. We further report on its anti-parasitic activity against Trypanosoma brucei with an IC50 value of 5 mu M and without cytotoxic effects against J774.1 macrophages at 100 mu M concentration. Plakortide E was isolated from the sponge Plakortis halichondroides using enzyme assay-guided fractionation and identified by NMR spectroscopy and mass spectrometry. Furthermore, enzyme kinetic studies confirmed plakortide E as a non-competitive, slowly-binding, reversible inhibitor of rhodesain.
Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities.
2015
Several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. The new compounds were tested for their activities against one strain of the causative organism of Malaria tropica, Plasmodium falciparum K1, which is resistant against chloroquine and pyrimethamine. In addition, their cytotoxicity and their activity against the pathogen of the East African form of sleeping sickness, Trypanosoma brucei rhodesiense, were investigated. Structure-activity relationships are discussed considering data of readily prepared compounds. For the first time, a distinct in vivo activity was observed against Plasmodium berghei in a mouse model. The active compound was further investigated.
Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes
2018
Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, pro…
Development of novel 1,4-benzodiazepine-based Michael acceptors as antitrypanosomal agents
2016
Novel 1,4-benzodiazepines, endowed with a Michael acceptor moiety, were designed taking advantage of a computational prediction of their pharmacokinetic parameters. Among all the synthesized derivatives, we identified a new lead compound (i.e., 4a), bearing a vinyl ketone warhead and endowed with a promising antitrypanosomal activity against Trypanosoma brucei brucei (IC50 = 5.29 µM), coupled with a lack of cytotoxicity towards mammalian cells (TC50>100 µM).
In vitro and in silico studies of polycondensed diazine systems as anti-parasitic agents
2012
Abstract Parasitic diseases caused by protozoarian agents are still relevant today more than ever. Recently, we synthesized several polycondensed diazine derivatives by means 1,3-dipolar cycloaddition reactions. A broad selection of these compounds were submitted to in vitro biological screening against Plasmodium falciparum , Leishmania infantum , Trypanosoma brucei , and Trypanosoma cruzi , resulting active at micromolar level. Induced Fit Docking/MM-GBSA studies were performed giving interesting indications about the probable mechanism of action of the most active compounds
Predicting 19F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex
2020
Abstract The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the 19F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleepi…
Drug combination studies of curcumin and genistein against rhodesain of Trypanosoma brucei rhodesiense
2018
Curcumin and genistein are two natural products obtained from Curcuma longa L. and soybeans, endowed with many biological properties. Within the last years they were shown to possess also a promising antitrypanosomal activity. In the present paper, we investigated the activity of both curcumin and genistein against rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense; drug combination studies, according to Chou and Talalay method, allowed us to demonstrate a potent synergistic effect for the combination curcumin-genistein. As a matter of fact, with our experiments we observed that the combination index of curcumin-genistein is < 1 for the reduction from 10 to 90% of rhode…
Changing epidemiology of human brucellosis, Germany, 1962-2005
2007
This endemic occupational disease has become a foodborne and travel-associated zoonosis primarily affecting Turkish immigrants.
Endovascular Repair of Aortic Rupture Due to Brucella Aortitis. Case report and Review of the literature. VASA 2011;40:150-6. PMID:21500181
2011
Brucellosis is a zoonosis, caused by bacteria belonging to the genus Brucella. Aortic involvement is a rare complication, often following embolization from infective endocarditis. However, contiguous propagation from vertebral involvement may occur. We report the case of an 81 year old patient abruptly presenting with aortic rupture due to Brucella melitensis infection. The diagnosis of aortic rupture was made by CT. The patient underwent urgent endovascular treatment using endoprosthesis deployment in the abdominal aorta and iliac arteries. Long term antibiotic treatment was given. Resolution of the acute event was obtained without further surgical treatment. 18 months after endovascular t…
Comparison of loop-mediated isothermal amplification (LAMP) and PCR for the diagnosis of infection with Trypanosoma brucei ssp. in equids in The Gamb…
2020
Introduction:\ud Infection of equids with Trypanosoma brucei (T. brucei) ssp. is of socioeconomic importance across sub-Saharan Africa as the disease often progresses to cause fatal meningoencephalitis. Loop-mediated isothermal amplification (LAMP) has been developed as a cost-effective molecular diagnostic test and is potentially applicable for use in field-based laboratories.\ud \ud Part I:\ud Threshold levels for T. brucei ssp. detection by LAMP were determined using whole equine blood specimens spiked with known concentrations of parasites. Results were compared to OIE antemortem gold standard of T. brucei-PCR (TBR-PCR).\ud \ud Results I:\ud Threshold for detection of T. brucei ssp. on …