       Document 0607
 DOCN  M9640607
 TI    Inhibition of Plasmodium falciparum malaria using antisense
       oligodeoxynucleotides.
 DT    9604
 AU    Barker RH Jr; Metelev V; Rapaport E; Zamecnik P; Hybridon, Inc.,
       Worcester, MA 01605, USA.
 SO    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):514-8. Unique Identifier :
       AIDSLINE MED/96133967
 AB    We studied inhibition of growth of the malaria parasite Plasmodium
       falciparum in in vitro culture using antisense (AS)
       oligodeoxynucleotides (ODNs) against different target genes. W2 and
       W2mef strains of drug-resistant parasites were exposed to AS ODNs over
       48 hr, and growth was determined by microscopic examination and
       [3H]hypoxanthine incorporation. At ODN concentrations of 1 microM,
       phosphorothioate (PS) ODNs inhibited growth in a target-independent
       manner. However, between 0.5 and 0.005 microM, ODNs against
       dihydrofolate reductase, dihydropteroate synthetase, ribonucleotide
       reductase, the schizont multigene family, and erythrocyte binding
       antigen EBA175 significantly inhibited growth compared with a PS AS ODN
       against human immunodeficiency virus, two AS ODNs containing eight
       mismatches, or the sense strand controls (P < 0.0001). The IC50 was
       approximately 0.05 microM, whereas that for non-sequence-specific
       controls was 15-fold higher. PS AS ODNs against DNA polymerase alpha
       showed less activity than that for other targets, whereas a single AS
       ODN against triose-phosphate isomerase did not differ significantly from
       controls. We conclude that at concentrations below 0.5 microM, PS AS
       ODNs targeted against several malarial genes significantly inhibit
       growth of drug-resistant parasites in a nucleotide sequence-dependent
       manner. This technology represents an alternative method for identifying
       malarial genes as potential drug targets.
 DE    Animal  Base Sequence  DNA Polymerases/GENETICS  Genes, Structural,
       Protozoan  Malaria, Falciparum/THERAPY  Molecular Sequence Data
       Oligonucleotides, Antisense/*PHARMACOLOGY  Plasmodium
       falciparum/ENZYMOLOGY/*GROWTH & DEVELOPMENT  Protozoan Proteins/GENETICS
       Ribonucleotide Reductases/GENETICS  Tetrahydrofolate
       Dehydrogenase/GENETICS  Triosephosphate Isomerase/GENETICS  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

