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Plasmodium falciparum:Kinetic Interactions of WR99210 with Pyrimethamine-Sensitive and Pyrimethamine-Resistant Dihydrofolate Reductase

1997; Elsevier BV; Volume: 87; Issue: 3 Linguagem: Inglês

10.1006/expr.1997.4228

1090-2449

Mohammad Hekmat-Nejad, Pradipsinh K. Rathod,

Trypanosoma species research and implications

With emerging drug resistance inPlasmodium falciparum,novel antifolates effective against pyrimethamine-resistant and cycloguanil-resistant dihydrofolate reductase (DHFR) are in demand. Based on structural similarity to cycloguanil, it has been proposed that WR99210, and its metabolic precursor PS-15, exerts selective antimalarial activity by binding tightly to both drug-sensitive and drug-resistant DHFR. In the present study, Linweaver–Burk plots and Ackermann–Potter plots reveal that both forms of malarial DHFR bind WR99210 at subnanomolar concentrations. It is not necessary to invoke an alternate target for WR99210 inP. falciparum.The present studies confirm that malarial DHFRs offer potential binding interactions in the folate-binding pocket distinct from those exploited by pyrimethamine and cycloguanil. These kinetic studies also provide a useful framework for the design and interpretation of future structural studies on drug-resistant DHFR fromP. falciparum.