Progresses in the Field of Drug Design to Combat Tropical Protozoan Parasitic Diseases

Abstract

The progresses made in the field of drug design to combat tropical protozoan parasitic diseases, such as Chagas' disease, leishmaniasis, and sleeping sickness are discussed. This article is focused on different approaches based on unique aspects of parasites biochemistry and physiology, selecting the more promising molecular targets for drug design. In spite of the enormous amount of work on the above features, the chemotherapy for all of these diseases remains unsolved. It is based on old and fairly not specific drugs associated, in several cases, with long-term treatments and severe side effects. Drug resistance and different strains susceptibility are further drawbacks of the existing chemotherapy. In this review article, a thorough analysis of selected molecular targets, mainly those that are significantly different compared with the mammalian host or, even, are not present in mammals would be described in terms of their potencial usefulness for drug design. Therefore, this article covers rational approaches to the chemotherapeutic control of these parasitic infections, such as the progresses in the search for novel metabolic pathways in parasites that may be essential for parasites survival but with no counterpart in the host. Ergosterol biosynthesis is a very interesting example. There are many enzymes involved in this biosynthetic pathway such us squalene synthase, farnesylpyrophosphate synthase, and other enzymes that are able to deplete endogenous sterols will be treated in this article. The enzymes involved in trypanothione biosynthesis, glutathionyl spermidine synthetase and trypanothione synthetase do not have an equivalent in mammals, and therefore it can be predicted low toxicity for compounds that are able to produce highly selective inhibition. Trypanothione reductase (TR), glyceraldehyde-3-phosphate dehydrogenase, dihydrofolate reductase, prenyltransferases, ornithine decarboxylase, etc, will be thoroughly analyzed. The design of specific inhibitors of such metabolic activities as possible means of controlling the parasites without damaging the hosts will be presented. The recent advances in the biochemistry of pathogenic parasites including the discovery of novel organelles will be discussed.

Fluorine-containing aryloxyethyl thiocyanate derivatives are potent inhibitors of Trypanosoma cruzi and Toxoplasma gondii proliferation

“…After 2 h of incubation at 37 °C in a 7% CO 2 atmosphere, cultures were washed twice with Hank's solution, and culture medium was replaced to remove extracellular parasites. At this time, 0.5-1 μCi of [5, H] uracil/well (specific activity, 40-50 Ci/mmol) and drug solutions in water were added. Two wells were left for infection control.…”

“…Two wells were left for infection control. Cultures were incubated for 72 h. Incorporation of the [5, H]uracil into trichloroacetic acid (TCA)-precipitable material was measured at day 3. The supernatants from the monolayers were transferred to glass tubes, the cells were dissolved with 1.3 ml of 1% sodium dodecyl sulfate containing 100 μg of cold uracil per ml, and the suspension was transferred to the glass tubes.…”

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

“…Interestingly, bisphosphonates also have antibacterial (17) and anticancer activities (18) and are able to stimulate ␥␦ T cells (19). Several of these compounds have antiparasitic action (20)(21)(22)(23). It was shown that the enzyme FPPS from these parasites is targeted by bisphosphonates (14).…”

2-Alkylaminoethyl-1,1-Bisphosphonic Acids Are Potent Inhibitors of the Enzymatic Activity of Trypanosoma cruzi Squalene Synthase

“…nhibitors of squalene synthase (SQS) have great potential not only as cholesterol-lowering agents (23) but also as antiparasitic drugs (16,37). In trypanosomatids, the enzyme catalyzes the first committed step in isoprenoid biosynthesis that leads to the formation of ergosterol instead of cholesterol such as occurs in mammals (37,38).…”