Disease relevance of WRA

• Enhanced in vitro activity of WR99210 in combination with dapsone against Mycobacterium avium complex [1].
• There was a mean of approximately 35 million parasites in control mice as contrasted with approximately 2 million parasites in mice treated with 1.25 mg WR99210/kg of body weight in a representative experiment (P < 0.05) [2].
• Efficacy of intraperitoneal administration of WR99210 and peroral administration of PS-15 demonstrate the potential usefulness of this class of compounds in treatment of toxoplasmosis administered either parenterally or perorally [2].
• WR99210 has high efficacy and relatively low toxicity because of its substantial effect on T. gondii dihydrofolate reductase (DHFR) but not the mammalian host DHFR [2].
• The experimental drug WR99210 efficiently killed all three yeast strains (IC50 about 10(-8) M) but the pyrR strains showed collateral hypersensitivity to drug [3].

High impact information on WRA

• Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax [4].
• Human DHFR was found to fully negate the antiparasitic effect of WR99210, thus demonstrating that the only significant action of WR99210 is against parasite DHFR [5].
• Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites [6].
• Administration of WR99210 parenterally (i.e., intraperitoneally) reduced the mean number of RH strain tachyzoites present in peritoneal fluid substantially 4 days after intraperitoneal infection of mice [2].
• The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine] inhibits Toxoplasma gondii in vitro at nanomolar levels (P < 0.05) [2].

Biological context of WRA

• This result suggests that WR99210 and related compounds will be clinically effective against quadruple mutants currently found in Southeast Asia and South America and against most novel alleles that could be selected on the background of the triple mutant genotype now prevalent in East Africa [7].
• Human dihydrofolate reductase (hdhfr) and Toxoplasma gondii dihydrofolate reductase-thymidylate synthase (Tgdhfr-ts) conferred drug resistance to WR99210 and pyrimethamine, respectively, when introduced as episomes [8].
• We were also able to generate and select transgenic parasites harbouring only a single copy of hDHFR targeted into their genome, despite the fact that these parasites showed only a fivefold increase in resistance to WR99210 compared to the parental parasites [9].
• An amino acid substitution in the Babesia bovis dihydrofolate reductase-thymidylate synthase gene is correlated to cross-resistance against pyrimethamine and WR99210 [10].

Anatomical context of WRA

• Serum drug concentrations provided further evidence that PS-15 was absorbed far better from the gastrointestinal tract than WR99210 [11].

Associations of WRA with other chemical compounds

• To investigate suggestions that WR99210 and proguanil act against a target other than the reductase moiety of the P. falciparum bifunctional DHFR-thymidylate synthase enzyme, we have transformed P. falciparum with a variant form of human DHFR selectable by methotrexate [5].
• The three DHFR inhibitors are the anticancer drug methotrexate, the antimicrobial trimethoprim and Br-WR99210, an analogue of the antimalarial agent WR99210 [12].
• The in vitro activities of the new biguanide PS-15 and its putative active metabolite, WR99210, were determined against seven different isolates or clones of Plasmodium falciparum [13].
• Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210 [14].
• Positive and negative selection of the thymidine kinase transformants with both ganciclovir and WR99210 resulted in the selection of parasites containing a genetic deletion of the Pfrh3 gene, the first targeted double crossover deletions in P. falciparum [15].

Gene context of WRA

• Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase [16].

Analytical, diagnostic and therapeutic context of WRA

• Analysis of plasma drug concentrations by high-performance liquid chromatography showed that the monkeys converted the WR250417 to its putative principal active metabolite WR99210 (a dihydrotriazine) [17].
• In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers [14].
• It was found that the minimum inhibitory concentrations of cycloguanil and WR99210 were not affected by physiological concentrations of folic or folinic acids in human serum [18].

References