Inhibitors of sterol and phospholipid biosynthesis in kinetoplastid
parasites such as Trypanosoma cruzi, the causative agent
of Chagas' disease, and different species of Leishmania
have potent and selective activity as chemotherapeutic agents in
vitro and in vivo. Recent work with the sterol
C14α-demethylase inhibitor D0870, a bis triazole derivative, showed
that this
compound is capable of inducing radical parasitological cure in murine
models
of both acute and chronic Chagas' disease.
Other inhibitors of this type, such as SCH 56592, have also shown curative,
rather than suppressive, activity against T.
cruzi in these models. Leishmania species have different
susceptibilities to sterol biosynthesis inhibitors, both in vitro
and
in vivo. Leishmania braziliensis promastigotes,
naturally resistant to C14α-demethylase inhibitors such as ketoconazole
and D0870, were susceptible to these drugs when used in combination with
the squalene epoxidase inhibitor terbinafine.
Inhibitors of Δ24(25)
sterol methyl transferase have been shown to act as potent antiproliferative
agents against Trypanosoma
cruzi, both in vitro and in vivo. New inhibitors
of this type which show enhanced activity and novel mechanisms of action
have been synthesized. Recent work has also demonstrated that this type
of
enzyme inhibitors can block sterol biosynthesis
and cell proliferation in Pneumocystis carinii, a fungal pathogen
which had previously been found resistant to other sterol
biosynthesis inhibitors. Ajoene, an antiplatelet compound derived from
garlic,
was shown to have potent antiproliferative
activity against epimastigotes and amastigotes of Trypanosoma cruzi
in vitro; this activity was associated with a significant
alteration of the phospholipid composition of the cells with no significant
effects on the sterol content. In addition,
alkyllsophospholipids such as ilmofosine, miltefosine and edelfosine have
been shown to block the proliferation of T. cruzi
and Leishmania and alter both the phospholipid and sterol composition.
These results indicate the potential of lipid
biosynthesis inhibitors as useful therapeutic agents in the treatment of
leishmaniasis and Chagas' disease.
Sterol biosynthesis and sterol uptake in the fungal pathogen Pneumocystis carinii
