The Importance of Targeting Lipid Metabolism in Parasites for Drug Discovery

The protozoan parasites that cause African sleeping sickness in sub-Saharan
Africa (Trypanosoma brucei), Chagas disease in Central and South America (Trypanosoma cruzi), “Old World” cutaneous leishmaniasis in the Middle
East, and “New World” visceral leishmaniasis (kala-azar) in East Africa, South
America, and Southeast Asia (various Leishmania species) are among the most
neglected diseases on the planet. Together with malaria caused by Plasmodium
spp. and related apicomplexans Toxoplasma and Cryptosporidium, millions of
people are affected representing a huge percentage of theworld’s disease burden.
Drugs that exist for the treatment of these diseases have low efficacy, high toxicity (at levels that would be unacceptable in the developed world), and fall well below the standards of modern medicine; increasing levels of drug resistance also pose a progressively serious problem. There is clearly an urgent need to identify new drugs and new drug targets.The current status of these drug discovery efforts for some of these diseases have recently been reviewed [1–4].
In the drug discovery process, selecting the best drug targets is crucial for maximizing chances of success. Lipid metabolism is an essential process for cell
types whose evolutionary success is based upon rapid proliferation and/or differentiation.
In this regard, there are similarities in the rapid proliferation and high
metabolic rate of both tumor cells and protozoan parasites. Lipids are crucial to
parasites as they are used as structural components of membranes, energy stores, pathogenic factors, and signaling molecules. As such, they depend upon a wide variety of systems for the uptake and metabolism of these molecules to satisfy this demand, which can dramatically vary during life cycle and morphological changes. The notable dependence on lipid resources for parasite survival in their hosts has and will continue to create prospects to restrict parasite growth and cure infections. Identified lipid metabolism in these parasites reveals that they are auxotrophic for many lipid precursors, which force them to meet their high demand for lipids through networks of both de novo synthesis and scavenging. This provides the scientific community with opportunities to exploit these “Achilles heels” for effective drug discovery purposes.