Microsoft Word - QGPPaper.doc

Hadronic matter at normal energy densities is composed of confined, color neutral quarks and gluons. At very high energy densities, theoretical models predict a transition should occur wherein the hadrons "melt" together to form a weakly coupled deconfined plasma of quarks and gluons, i.e. quark gluon plasma (QGP). Experimental evidence suggests that the state of matter formed in the high energy Au-Au collisions at the Relativistic Heavy Ion Collider (RHIC) at Brookhaven National Laboratory is actually a strongly coupled plasma. In this paper I shall discuss some of the basic features of QGP as well as experimental evidence from the RHIC experiments (PHENIX, STAR, BRAHMS, PHOBOS) that supports its existence

Isoprenoid Biosynthesis Pathway as a Drug Target for Bisphosphonates: Transcriptional Profile Investigation

158 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.Bisphosphonates are known as potent inhibitors of the enzyme farnesyl diphosphate synthase (FPPS) and are clinically used to treat bone related disorders such as osteoporosis and bone cancer. Here we describe the development, testing and study of the mechanism of action of novel bisphosphonates as anti-bacterial and anti-cancer agents. We identified a FPPS bisphosphonate inhibitor which in combination with the phosphonate drug fosmidomycin exerted a potent synergistic effect in Escherichia coli. Additionally, we designed novel groups of bisphosphonates which are ∼10-1000 fold more potent against tumor cell lines than conventional bisphosphonates due to their ability to inhibit more than one enzyme in the mevalonate pathway.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates.

Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi). Here, we show that non-hydrolyzable analogues of PPi, bisphosphonates, are potent inhibitors of T. cruzi hexokinase (TcHK). We determined the activity of 42 bisphosphonates against TcHK, and the IC(50) values were used to construct pharmacophore and comparative molecular similarity indices analysis (CoMSIA) models for enzyme inhibition. Both models revealed the importance of electrostatic, hydrophobic, and steric interactions, and the IC(50) values for 17 active compounds were predicted with an average error of 2.4x by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi

Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole

There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca2+ homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca2+ homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.Fil: Benaim, Gustavo. Universidad Central de Venezuela, Facultad de Ciencias; Venezuela. Instituto Internacional de Estudios Avanzados; VenezuelaFil: Sanders, John M.. University of Illinois at Urbana; Estados UnidosFil: Garcia Marchán, Yael. Universidad Central de Venezuela, Facultad de Ciencias; VenezuelaFil: Colina, Claudia. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Lira, Renee. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Caldera, Aura R.. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Payares, Gilberto. Universidad Central de Venezuela. Facultad de Ciencias; VenezuelaFil: Sanoja, Cristina. Universidad Central de Venezuela. Facultad de Ciencias; VenezuelaFil: Burgos, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Leon-Rossell, Annette. University of Illinois. Urbana - Champaign; Estados UnidosFil: Concepcion, Juan Luis. Universidad de los Andes; VenezuelaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Levin, Mariano Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Institut Cochin; FranciaFil: Oldfield, Eric. University of Illinois. Urbana - Champaign; Estados UnidosFil: Urbina, Julio A.. Instituto Venezolano de Investigaciones Científicas; Venezuel