The Experts below are selected from a list of 33 Experts worldwide ranked by ideXlab platform
Kenneth Stuart - One of the best experts on this subject based on the ideXlab platform.
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inhibition of isoleucyl trna synthetase as a potential treatment for human african trypanosomiasis
Journal of Biological Chemistry, 2013Co-Authors: Igor Cestari, Kenneth StuartAbstract:Trypanosoma brucei sp. causes human African trypanosomiasis (HAT; African sleeping sickness). The parasites initially proliferate in the Hemolymphatic System and then invade the central nervous System, which is lethal if not treated. New drugs are needed for HAT because the approved drugs are few, toxic, and difficult to administer, and drug resistance is spreading. We showed by RNAi knockdown that T. brucei isoleucyl-tRNA synthetase is essential for the parasites in vitro and in vivo in a mouse model of infection. By structure prediction and experimental analysis, we also identified small molecules that inhibit recombinant isoleucyl-tRNA synthetase and that are lethal to the parasites in vitro and highly selective compared with mammalian cells. One of these molecules acts as a competitive inhibitor of the enzyme and cures mice of the infection. Because members of this class of molecules are known to cross the blood-brain barrier in humans and to be tolerated, they may be attractive as leading candidates for drug development for HAT.
M Dumas - One of the best experts on this subject based on the ideXlab platform.
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treatment perspectives for human african trypanosomiasis
Fundamental & Clinical Pharmacology, 2003Co-Authors: Bernard Bouteille, Odile Oukem, Sylvie Bisser, M DumasAbstract:Human African trypanosomiasis (HAT), or sleeping sickness, is currently on the rise. HAT develops in two stages, the first involving the Hemolymphatic System, and the second, the neurological System. Left untreated, HAT is invariably fatal. There have been no therapeutic advances in more than 40 years. Stage 1 can be treated with pentamidine and suramin, but stage 2 can only be treated with melarsoprol, a toxic arsenic derivative that has a 2-12% incidence of fatal side-effects (encephalopathy). Eflornithine has never achieved widespread use because it is difficult to administer under field conditions. Nifurtimox has been used successfully in the treatment of American trypanosomiasis, or Chagas disease, but only in small studies or as a compassionate use treatment. There is little research and development for new drugs in this area: only one prodrug is in the clinical development phase, a pentamidine analog that offers hope for the replacement of injectable pentamidine with an orally administered drug. Current efforts appear to be focused on reevaluating older drugs. A course of treatment with melarsoprol for 10 days at 2.2 mg/kg/day is now in the multicenter evaluation phase. Orally administered eflornithine is also slated for reevaluation. In addition, studies of drug combinations are recommended to determine possible combined or synergistic effects and find ways to reduce toxicity.
Bernard Bouteille - One of the best experts on this subject based on the ideXlab platform.
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treatment perspectives for human african trypanosomiasis
Fundamental & Clinical Pharmacology, 2003Co-Authors: Bernard Bouteille, Odile Oukem, Sylvie Bisser, M DumasAbstract:Human African trypanosomiasis (HAT), or sleeping sickness, is currently on the rise. HAT develops in two stages, the first involving the Hemolymphatic System, and the second, the neurological System. Left untreated, HAT is invariably fatal. There have been no therapeutic advances in more than 40 years. Stage 1 can be treated with pentamidine and suramin, but stage 2 can only be treated with melarsoprol, a toxic arsenic derivative that has a 2-12% incidence of fatal side-effects (encephalopathy). Eflornithine has never achieved widespread use because it is difficult to administer under field conditions. Nifurtimox has been used successfully in the treatment of American trypanosomiasis, or Chagas disease, but only in small studies or as a compassionate use treatment. There is little research and development for new drugs in this area: only one prodrug is in the clinical development phase, a pentamidine analog that offers hope for the replacement of injectable pentamidine with an orally administered drug. Current efforts appear to be focused on reevaluating older drugs. A course of treatment with melarsoprol for 10 days at 2.2 mg/kg/day is now in the multicenter evaluation phase. Orally administered eflornithine is also slated for reevaluation. In addition, studies of drug combinations are recommended to determine possible combined or synergistic effects and find ways to reduce toxicity.
Martin E Rottenberg - One of the best experts on this subject based on the ideXlab platform.
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distinct toll like receptor signals regulate cerebral parasite load and interferon α β and tumor necrosis factor α dependent t cell infiltration in the brains of trypanosoma brucei infected mice
The Journal of Infectious Diseases, 2012Co-Authors: Daniel Ndem Amin, Suman K Vodnala, Willias Masocha, Bo Sun, Krister Kristensson, Martin E RottenbergAbstract:Infections with subspecies of the extracellular parasite Trypanosoma brucei cause African trypanosomiasis, a disease that affects both humans (sleeping sickness) and animals. During the early stage of human African trypanosomiasis the parasites invade the Hemolymphatic System, and during the late meningoencephalitic stage severe signs of nervous System involvement are observed [1–3]. In a mouse model of the disease, T. brucei brucei penetrate the blood-brain barrier (BBB) at a late stage and can enter the brain parenchyma [4]. Within the CNS, activation of white blood cell infiltrates and resident cells probably leads to the nervous System disease [5]. The innate immune System has evolved several strategies of self-nonself discrimination that are based on the recognition of molecular patterns demarcating infectious nonself. Different Toll-like receptors (TLRs), by recognizing diverse pathogen-associated molecular patterns of microbes, activate innate immunity and may initiate the subsequent development of adaptive immunity. TLR agonists stimulate the secretion of proinflammatory cytokines and type I interferons (IFN-α/β) that are involved not only in protection against infections but also in infection-mediated pathology. The development of adaptive immune responses is at least in part mediated through the ability of the innate receptor signaling to activate and stimulate the migration of antigen-presenting cells into the lymph nodes [6]. The binding of TLRs (except TLR3) by their corresponding ligands results in the recruitment of the intracellular adaptor molecule MyD88. Myd88–/– animals are highly susceptible to infection with a wide variety of different pathogens, including infection with T. brucei brucei [7–9]. We have shown elsewhere that the T-cell–derived cytokine IFN-γ, as well as the IFN-inducible chemokine CXCL10, promote the penetration of T cells and parasites in the brain [4, 10], suggesting also that parasites follow T cells during their brain invasion across the BBB. Despite the accepted view that signaling from specific innate immune receptors are required to activate and determine the quality of T-cell responses, the role of innate immunity in T-cell–mediated central nervous System (CNS) diseases, such as sleeping sickness, is poorly understood. In the current study, we investigated whether signals emanating from TLR control the accumulation of T cells and parasites in the brain parenchyma. We demonstrate that TLR signaling regulates the penetration of T cells and parasites across the BBB and controls survival of the latter in the brain parenchyma through distinct mechanisms.
Igor Cestari - One of the best experts on this subject based on the ideXlab platform.
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inhibition of isoleucyl trna synthetase as a potential treatment for human african trypanosomiasis
Journal of Biological Chemistry, 2013Co-Authors: Igor Cestari, Kenneth StuartAbstract:Trypanosoma brucei sp. causes human African trypanosomiasis (HAT; African sleeping sickness). The parasites initially proliferate in the Hemolymphatic System and then invade the central nervous System, which is lethal if not treated. New drugs are needed for HAT because the approved drugs are few, toxic, and difficult to administer, and drug resistance is spreading. We showed by RNAi knockdown that T. brucei isoleucyl-tRNA synthetase is essential for the parasites in vitro and in vivo in a mouse model of infection. By structure prediction and experimental analysis, we also identified small molecules that inhibit recombinant isoleucyl-tRNA synthetase and that are lethal to the parasites in vitro and highly selective compared with mammalian cells. One of these molecules acts as a competitive inhibitor of the enzyme and cures mice of the infection. Because members of this class of molecules are known to cross the blood-brain barrier in humans and to be tolerated, they may be attractive as leading candidates for drug development for HAT.