Inhibitors of phospholipids

Alkyl-lysophospholipids (ALP) are synthetic analogs of lysophospholipids that have been shown to be effective in vitro and in vivo on T. cruzi and trypanosoma- tides. Miltefosine, one of its representatives, has been used orally in visceral leishmaniasis with good results. ALP blocks selectively the biosynthesis of phosphatydil-coline (PC) of T. cruzi through the transmethylation of the Greenberg pathway, in contrast to the vertebrate host where the Kennedy pathway of CDP choline is predominant.²⁰

Inhibitors of pyrophosphate metabolism

The inorganic pyrophosphates (P₂ O₇^4_; PPi) and other short-chain tri- and tetra- polyphosphates are those that have the greatest energy of phosphate compounds in trypanosomatides (T. cruzi, T. brucei, and L. mexicana) and apicomplexa parasites (Toxoplasma gondii). They have 10—15 times more energy than ATP. PPi is distributed throughout the cell, but is concentrated in the acidocalcisomes, specialized acid vacuoles with large quantities of Ca²¹. PPi enzymes of T. cruzi, such as a proton-translocating pyrophosphose in acidocalcisomes and pyruvate phosphate dikinase in glycosomes, suggest that PPi has an important role in parasite survival. This has been confirmed by the observation that pamidronate, alendronate, and risedronate, contain biphosphonates, nonmetabolizable pyrophosphate analogs currently used in human medicine in alterations of bone reabsorption, which selectively inhibit the proliferation of intracellular amasti- gotes and tachyzoites of T. gondii. It has been demonstrated that residronate (Ris) acts in vitro on epimastigotes and cell cultures of amastigotes of T. cruzi, also reducing the infection in mice with acute infection, eliminating almost completely the parasitemias and intracellular amastigote forms. This drug inhibits farnesyl pyrophosphate synthase of the parasite, blocking the biosynthesis of polyisopre- noids.³⁰ It has not yet been used in humans. One inhibitor of farnesyltransferase, Tipifarnib (R115777), which inhibits cytochrome P450 sterol demethylase (CYP₅₁), is a potential target against T. cruzi, but in spite of its success in experimental animals it has not been applied to humans.³¹

The sterol 14-demethylase of T. cruzi has been studied (TCCYP51). It is related catalytically to the CYP51 of animal fungi.^32,33 Inhibition by obtusifoliol and its analogs enormously reduces enzyme activity. TCCYP51 constitutes a potential target against T. cruzi; however, to date no experimental surveys have performed to establish its efficacy in animals.