Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs

Science

Volumn 285, Issue 5433, 1999, Pages 1573-1576

  Jomaa, Hassan ^a   Wiesner, Jochen ^a   Sanderbrand, Silke ^a   Altincicek, Boran ^a   Weidemeyer, Claus ^a   Hintz, Martin ^a   Türbachova, Ivana ^b   Eberl, Matthias ^a   Zeidler, Johannes ^c   Lichtenthaler, Hartmut K ^c   Soldati, Dominique ^b   Beck, Ewald ^a  

^a JUSTUS LIEBIG UNIVERSITY   (Germany)

^b Zentrum für Molekulare Biologie   (Germany)

^c UNIVERSITY OF KARLSRUHE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

1 DEOXYXYLULOSE 5 PHOSPHATE; 3 (N ACETYL N HYDROXYAMINO)PROPYLPHOSPHONIC ACID; ANTIMALARIAL AGENT; FOSMIDOMYCIN; ISOMERASE; ISOPRENOID; MEVALONIC ACID; SYNTHETASE; UNCLASSIFIED DRUG; XYLULOSE;

AMINO ACID SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBIOTIC SENSITIVITY; ANTIMALARIAL ACTIVITY; ARTICLE; DRUG EFFECT; DRUG EFFICACY; ENZYME INHIBITION; INTRAPERITONEAL DRUG ADMINISTRATION; MALARIA FALCIPARUM; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; ORAL DRUG ADMINISTRATION; PARASITE DEVELOPMENT; PLASMODIUM FALCIPARUM; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; STEROL SYNTHESIS;

ALDOSE-KETOSE ISOMERASES; AMINO ACID SEQUENCE; ANIMALS; ANTIMALARIALS; CLONING, MOLECULAR; ENZYME INHIBITORS; FOSFOMYCIN; GENES, PROTOZOAN; HEMITERPENES; MALARIA; MALARIA, FALCIPARUM; MEVALONIC ACID; MICE; MOLECULAR SEQUENCE DATA; MULTIENZYME COMPLEXES; ORGANELLES; ORGANOPHOSPHORUS COMPOUNDS; OXIDOREDUCTASES; PENTOSEPHOSPHATES; PLASMODIUM FALCIPARUM; RECOMBINANT PROTEINS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; TERPENES;

ANIMALIA; PLASMODIUM FALCIPARUM; PLASMODIUM VINCKEI; RODENTIA;

EID: 0033520336     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.285.5433.1573     Document Type: Article

References (35)

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16. 2-terminal and COOH-terminal parts of the P. falciparum DOXP synthase were identified [the following were from the TIGR database: PNAEL30TR, PNAEP81TF, and PNAEP81TR (contiguous sequence 749); the following was from the database at the Sanger Centre (available at www.sanger.ac.uk/Projects/P_falciparum/ftp.shtml): M13Q12a4.plt (contiguous sequence 09086)]. A central part of the DOXP synthase gene missing in the databases was amplified with the primers PfSYNfor (5′-AATAAATTAAAAAGAGCTACTGTTCTTC-3′) and PfSYNrev (5′-TAAGATAAATCATATATACCTTGATGTG-3′) (GenBank accession number AF1118141). For sequencing, the PCR products were cloned with the TA-doning kit (Invitrogen).
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20. -) were transfected with this construct by electroporation [D. Soldati and J. C Boothroyd, Science 260, 349 (1993)]. Intracellular parasites grown for 24 hours in human foreskin fibroblasts on glass slides were fixed with 4% paraformaldehyde and 0.05% glutaraldehyde for 20 min. After fixation, slides were briefly rinsed in phosphate-buffered saline (PBS) and 0.1 M glycine and mounted in Vectashield. Micrographs were obtained with a Axiophot microscope (Zeiss) equipped with a camera (type CH-250, Photometries, Tucson, AZ ). Adobe Photoshop (Adobe Systems, Mountain View, CA) was used for image processing. The expression of GFP coupled to the leader sequence of DOXP reductoisomerase appears to be toxic for T. gondii because all positive transfectants failed to divide at 24 and 48 hours after transfection.
21. -) were transfected with this construct by electroporation [D. Soldati and J. C Boothroyd, Science 260, 349 (1993)]. Intracellular parasites grown for 24 hours in human foreskin fibroblasts on glass slides were fixed with 4% paraformaldehyde and 0.05% glutaraldehyde for 20 min. After fixation, slides were briefly rinsed in phosphate-buffered saline (PBS) and 0.1 M glycine and mounted in Vectashield. Micrographs were obtained with a Axiophot microscope (Zeiss) equipped with a camera (type CH-250, Photometries, Tucson, AZ ). Adobe Photoshop (Adobe Systems, Mountain View, CA) was used for image processing. The expression of GFP coupled to the leader sequence of DOXP reductoisomerase appears to be toxic for T. gondii because all positive transfectants failed to divide at 24 and 48 hours after transfection.
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34. Single-letter abbreviations for the amino acid residues are as follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
35. We thank the board of directors of the Academic Hospital Centre of the University of Giessen for their generous support; U. Jost, D. Henschker, I. Steinbrecher, and R. Füllkrug for technical assistance; and our colleagues from the local Institute of Clinical Immunology and Transfusion Medicine for supplying blood components. Sequence data for P. falciparum chromosome 13 were obtained from the Sanger Centre (available at www.sanger.ac.uk/Projects/PJalciparum/). Sequencing of P. falciparum chromosome 13 was accomplished as part of the Malaria Genome Project, with support by the Wellcome Trust Preliminary sequence data for P. falciparum chromosome 14 were obtained from TIGR (available at www.tigr.org). Sequencing of chromosome 14 was part of the international Malaria Genome Sequencing Project and was supported by awards from the Burroughs Wellcome Fund and the U.S. Department of Defense.