Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase

The lack of suitable antimalarial agents to replace chloroquine and pyrimethamine/sulfadoxine threatens efforts to control the spread of drug-resistant strains of the malaria parasite Plasmodium falciparum. Here we describe a transformation system, involving WR99210 selection of parasites transforme...

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Bibliographic Details
Published in:Molecular pharmacology 1998-12, Vol.54 (6), p.1140-1147
Main Authors: Fidock, D A, Nomura, T, Wellems, T E
Format: Article
Language:English
Subjects:
Animals
Antimalarials - pharmacology
Folic Acid Antagonists - pharmacology
Genetic Complementation Test
Humans
Hypoxanthine - metabolism
Inhibitory Concentration 50
Methotrexate - pharmacology
Mutation
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Plasmodium falciparum - genetics
Proguanil - pharmacology
Tetrahydrofolate Dehydrogenase - biosynthesis
Tetrahydrofolate Dehydrogenase - genetics
Triazines - pharmacology
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Summary:The lack of suitable antimalarial agents to replace chloroquine and pyrimethamine/sulfadoxine threatens efforts to control the spread of drug-resistant strains of the malaria parasite Plasmodium falciparum. Here we describe a transformation system, involving WR99210 selection of parasites transformed with either wild-type or methotrexate-resistant human dihydrofolate reductase (DHFR), that has application for the screening of P. falciparum-specific DHFR inhibitors that are active against drug-resistant parasites. Using this system, we have found that the prophylactic drug cycloguanil has a mode of pharmacological action distinct from the activity of its parent compound proguanil. Complementation assays demonstrate that cycloguanil acts specifically on P. falciparum DHFR and has no other significant target. The target of proguanil itself is separate from DHFR. We propose a strategy of combination chemotherapy incorporating the use of multiple parasite-specific inhibitors that act at the same molecular target and thereby maintain, in combination, their effectiveness against alternative forms of resistance that arise from different sets of point mutations in the target. This approach could be combined with traditional forms of combination chemotherapy in which two or more compounds are used against separate targets.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.54.6.1140