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  • 1
    ISSN: 1365-2958
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: Melaminophenyl arsenical drugs are a mainstay of chemotherapy against late-stage African sleeping sickness, but drug resistance is increasingly prevalent. We describe here the characterization of two genes encoding putative metal–thiol conjugate transporters from Trypanosoma brucei. The two proteins, TbMRPA and TbMRPE, were each overexpressed in trypanosomes, with or without co-expression of two key enzymes in trypanothione biosynthesis, ornithine decarboxylase and gamma-glutamyl-cysteine synthetase. Overexpression of gamma-glutamyl-cysteine synthetase resulted in a twofold increase in cellular trypanothione, whereas overexpression of ornithine decarboxylase had no effect on the trypanothione level. The overexpression of TbMRPA resulted in a 10-fold increase in the IC50 of melarsoprol. The overexpression of the trypanothione biosynthetic enzymes alone gave two- to fourfold melarsoprol resistance, but did not enhance resistance caused by MRPA. Overexpression of TbMRPE had little effect on susceptibility to melarsoprol but did give two- to threefold resistance to suramin.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 0887-3585
    Keywords: X-ray crystallography ; disulfide oxidoreductases ; FAD ; NADPH ; drug target ; Chagas' disease ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The three-dimensional structure of trypanothione reductase (TR) (EC 1.6.4.8) from Trypanosoma cruzi has been solved at 0.33 nm resolution by molecular replacement using the structure of C. fasciculata TR as a starting model. Elucidation of the T. cruzi TR structure represents the first step in the rational design of a drug against Chagas' disease. The structure of T. cruzi TR is compared with those of C. fasciculata TR as well as human and E. coli glutathione reductase (GR). In the FAD-binding domain, TR has two insertions, each about 10 residues long, which do not occur in GR. The first one is a rigid loop stabilizing the position of helix 91-117 which is responsible for the wider active site of TR as compared to GR. The second insertion does not occur where it is predicted by sequence alignment; rather the residues extend three strands of the 4-stranded β-sheet by one or two residues each. This increases the number of hydrogen bonds within the sheet structure. The structure of the NADPH.TR complex has been solved at 0.33 nm resolution. The nicotinamide ring is sandwiched between the flavin ring and the side chain of Phe-198 which undergoes the same conformational change upon coenzyme binding as Tyr-197 in GR. In addition to Arg-222 and Arg-228, which are conserved in TR and GR, Tyr-221 - the last residue of the second β-sheet strand of the βαβ dinucleotide binding fold - is in hydrogen bonding distance to the 2′ phosphate group of NADPH. © 1994 John Wiley & Sons, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0887-3585
    Keywords: X-ray crystallography ; flavoenzyme ; drug target ; Trypanosoma cruzi ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The three-dimensional structure of the complex between Trypanosoma cruzi trypanothione reductase (TR) (EC 1.6.4.8) and the antiparasitic drug mepacrine (quinacrine) has been solved at 2.9 Å resolution. Mepacrine is a competitive inhibitor of TR but does not affect human glutathione reductase (GR), a closely related host enzyme. Of particular importance for inhibitor binding are four amino acid residues in the disulfide substrate-binding site of TR that are not conserved in human GR, namely, Glu-18 (Ala-34 in GR), Trp-21 (Arg-37), Ser-109 (Ile-113), and Met-113 (Asn-117).The acridine ring of mepacrine is fixed at the active site close to the hydrophobic wall formed by Trp-21 and Met-113. Specific pairwise interactions between functional groups of the drug and amino acid side chains include the ring nitrogen and Met-113, the chlorine atom and Trp-21, and the oxymethyl group and Ser-109. The alkylamino chain of mepacrine points into the inner region of the active site and is held in position by a solvent-mediated hydrogen bond to Glu-18.The structure of the complex shows for the first time the atomic interactions between TR and an inhibitory ligand. This is a crucial step towards the rational design of inhibitors that might be suited as drugs against Chagas' disease. © 1996 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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  • 4
    ISSN: 0570-0833
    Keywords: drug design ; enzyme inhibitors ; Drug research ; Medicinal chemistry ; Malaria ; Enzyme inhibitors ; Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Viewed globally, parasitic diseases such as malaria and Chagas' cardiopathy pose an increasing threat to human health and welfare. Recognition of this problem and the challenge of synthesizing a quinine-like antimalarial agent sparked off the development of the chemical industry about 100 years ago. Our contribution deals with aspects of drug design, a young branch of pharmaceutical chemistry. As drug targets the flavoenzyme, glutathione reductase, and the recently discovered parasite enzyme, trypanothione reductase, were chosen. Based on the knowledge of the structure of these molecules, the modeling of enzyme inhibitors as potential chemotherapeutic agents against parasites has become possible. In addition, biochemical and clinical observations are considered since chemical principles of biological evolution can serve as guidelines for the pharmaceutical chemists. The picture shows two erythrocytes destroyed by malaria parasites. In the center of the photograph a parasite is just leaving its host cell through the ruptured cell membrane. Its target could be a neighboring healthy erythrocyte.
    Additional Material: 5 Ill.
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  • 5
    ISSN: 0044-8249
    Keywords: Drug-Design ; Enzyminhibitoren ; Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Global gesehen, sind parasitäre Erkrankungen wie die Malaria oder die Chagas-Herzkrankheit die größte Bedrohung für eine menschenwürdige Existenz. Das Bewußtsein für dieses Problem und die Herausforderung, eine chininähnliche Substanz gegen die Malaria zu synthetisieren, prägten vor etwa 100 Jahren die Anfänge und die Entwicklung der chemischen Industrie. In dieser Übersicht werden Aspekte des Drug-Designs, einer jungen Disziplin der pharmazeutischen Chemie, behandelt. Im Mittelpunkt stehen das Flavoenzym Glutathion-Reduktase und das vor wenigen Jahren entdeckte Parasitenenzym Trypanothion-Reduktase. Anhand der Strukturen dieser Moleküle wurden Enzyminhibitoren als potentielle Chemotherapeutica gegen Parasiten modelliert. Diskutiert werden auch biochemische und klinische Befunde als Grundlage für das Drug-Design; denn gerade auf physikochemischer submolekularer Ebene muß der Chemiker den Entwicklungsvorsprung der belebten Natur respektieren und nutzen. - Das Bild links zeigt zwei von Malariaerregern zerstörte Erythrocyten. In der Bildmitte verläßt ein Parasit gerade seine Wirtszelle durch eine Bresche in der Zellmembran. Sein Ziel könnte der nächstliegende gesunde Erythrocyt (rechts unten) sein.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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