Activity of P536, a UDP-glucose analog, against Trypanosoma cruzi

Abstract

. Chem. 28:40-46, 1985), has a potent and selective activity against the intracellular and extracellular stages of Trypanosoma cruzi in vitro. It had a 50% inhibitory concentration of less than 5 ,Ig/ml for T. cruzi extracellular cultured forms (epimastigote) and of 25 ,ug/ml for T. cruzi intracellular forms (amastigote) growing inside J774G8 macrophagelike cells. In contrast, the 50% inhibitory concentration was 100 ,ug/ml or greater for cultured mammalian cells and 180 ,ug/ml for the proliferation of mouse spleen lymphocytes. Furthermore, the addition of P536 (50 ,ug/mI) The flagellated protozoan Trypanosoma cruzi is the causal agent of American trypanosomiasis or Chagas' disease (1, 12). T. cruzi exists as epimastigotes (preinfective forms) and metacyclic trypomastigotes (infective forms). The latter are transmitted to mammals by Triatominae insects, where they differentiate into a nonreplicative bloodstream form (trypomastigote) that can infect some types of host cells dividing intracellularly as amastigotes (12).Few drugs are available for the treatment of T. cruzi infections, although heterocyclic drugs such as nifurtimox and benznidazole can ameliorate Chagas' disease (8). However, they have little or no effect on the chronic phase of the disease (14). The intracellular stage is perhaps the most important, since the protozoan is protected not only from the immune system but also from the action of some drugs (8,12). Alternatively, the host cell membrane may be a barrier impermeable to the drug, or the host cell may inactivate it. Therefore, drugs that affect the intracellular forms of the parasite are of particular interest (5,14). In the present study we describe the antitrypanosomic activity of P536, a compound synthesized as an analog of UDP-glucose and previously described as an antiviral agent (9). MATERIALS AND METHODSMaterials. The synthesis of the UDP-glucose analog P536 (Fig. 1) has been described previously (9). P536 was solubilized in water at 10 mM.Media and cells. Human epithelial carcinoma HeLa cells and African green monkey Vero cells were grown in Dulbecco modified Eagle (DME) medium (GIBCO Laboratories) supplemented with calf serum. Murine macrophage J774 68 cells were grown in DME medium plus 10% fetal calf serum (FCS) (GIBCO). Mouse spleen lymphocytes were obtained after removing the erythrocytes by hypotonic lysis and suspended in DME medium plus 5% FCS as described previously (2). T. cruzi, Tulahuen strain, kindly supplied by John David, was cultured continuously in cultured liver infusion-tryptose (LIT) medium supplemented with 10% * Corresponding author.FCS at 27°C, and harvested in the stationary phase as described previously (10). Under those conditions, the medium contained a mixture of the different stages (65 to 75% epimastigotes, 10 to 15% trypomastigotes, and 5 to 10% intermediate forms). A purified population of epimastigotes was obtained from experimental growing cultures which contained more than 99% epimastigotes (2).Infection of the J774 macrophage cell line with T. cr...

Antiparasitic Effects of the Intra-Golgi Transport Inhibitor Megalomicin

“…There is wide variation in the availability and efficacy of drugs for the therapy and prophylaxis of parasitic diseases, in both humans and domestic animals (10). There are still major deficiencies in antiparasite chemotherapy for human African trypanosomiasis (15), Chagas' disease (6,20), and leishmaniasis (14), among others. Available drugs are inadequate because of low efficacy, high toxicity, or the requirement of long courses of parenteral administration.…”