PLASMODIUM-FALCIPARUM - KINETIC INTERACTIONS OF WR99210 WITH PYRIMETHAMINE-SENSITIVE AND PYRIMETHAMINE-RESISTANT DIHYDROFOLATE-REDUCTASE

With emerging drug resistance in Plasmodium falciparum, novel antifola tes effective against pyrimethamine-resistant and cycloguanil-resistan t dihydrofolate reductase (DHFR) are in demand. Based on structural si milarity to cycloguanil, it has been proposed that WR99210, and its me tabolic precursor PS-I5, exerts selective antimalarial activity by bin ding tightly to both drug-sensitive and drug-resistant DHFR. In the pr esent study Linweaver-Burk plots and Ackermann-Potter plots reveal tha t both forms of malarial DHFR bind WR99210 at subnanomolar concentrati ons. It is not necessary to invoke an alternate target for WR99210 in P. falciparum. The present studies confirm that malarial DHFRs offer p otential binding interactions in the folate-binding pocket distinct fr om those exploited by pyrimethamine and cycloguanil, These kinetic stu dies also provide a useful framework for the design and interpretation of future structural studies on drug-resistant DHFR from P. falciparu m. (C) 1997 Academic Press.