Thematic review series: Lipid Posttranslational Modifications. Fighting parasitic disease by blocking protein farnesylation

Abstract

Protein farnesylation is a form of posttranslational modification that occurs in most, if not all, eukaryotic cells. Inhibitors of protein farnesyltransferase (PFTIs) have been developed as anticancer chemotherapeutic agents. Using the knowledge gained from the development of PFTIs for the treatment of cancer, researchers are currently investigating the use of PFTIs for the treatment of eukaryotic pathogens. This "piggy-back" approach not only accelerates the development of a chemotherapeutic agent for protozoan pathogens but is also a means of mitigating the costs associated with de novo drug design. PFTIs have already been shown to be efficacious in the treatment of eukaryotic pathogens in animal models, including both Trypanosoma brucei, the causative agent of African sleeping sickness, and Plasmodium falciparum, one of the causative agents of malaria. Here, current evidence and progress are summarized that support the targeting of protein farnesyltransferase for the treatment of parasitic diseases. Parasitic diseases continue to have a major impact on morbidity and mortality in tropical and subtropical regions. Among these, malaria causes $300 million infections annually, with 1-3 million deaths occurring in Africa (1). The emergence and spread of parasites resistant to existing antimalarial agents is largely responsible for the recent increase in malaria-related mortality. Another reemerging disease is African sleeping sickness (African trypanosomiasis), with an estimated 50,000 deaths in 2002 (1). The increasing burden of these diseases, along with the inadequacies of current drugs for African sleeping sickness in terms of safety, efficacy, and ease of administration, have led investigators to seek new chemotherapeutic agents (2, 3). Among the current drug targets under study are enzymes involved in protein prenylation, or the posttranslational modification of proteins by the covalent modification by isoprenyl lipids, C15 farnesyl and C20 geranylgeranyl (4-7). The isoprenyl lipid modification of proteins has been shown to be critical for various cellular activities in mammals and yeast, including proliferation and apoptosis (8, 9). Growth of the protozoan parasites has been shown to be severely impaired by the inhibition of protein farnesylation compared with mammalian cells, suggesting high potential of the enzyme protein farnesyltransferase (PFT) as an antiparasitic drug target (5, 10-13).The isoprenoid synthesis pathway from mevalonic acid in many eukaryotes, including trypanosomatids (or deoxyxylulose in Apicomplexa, including Plasmodium and Toxoplasma, and plants) is essential for the production of sterols, dolichol, ubiquinone, and other isoprene derivatives in many eukaryotic cells. Indeed, these pathways have been the study of recent efforts to develop other antiparasitic chemotherapeutic agents, especially the targeting of isoprenoid pyrophosphate synthesis by nitrogen-containing bisphosphonates (14-16). Organisms belonging to the group Apicomplexa contain the nonmevalonate pathway of iso...

Lipidomics of host–pathogen interactions

“…Lysobisphosphatidic acid and phosphoinositides regulate release of VSV nucleocapsid into cytoplasm [13] SigD/SopB is a type III bacterial derived phosphoinositide phosphatase [29,112] Molecular species of phosphatidylcholine and phosphatidylethanolamine are altered in host plasmamembrane after Plasmodium infection [116] GP Ethanolamine phospholipids required for Sindbis virus production [111] Intracellular mycobacteria release a heterogeneous mixture of lipids [27,113] Growth arrest of Plasmodium [117] and Toxoplasma [85] by disruption of phosphatidylcholine synthesis Semliki Forest virus mRNA capping enzyme requires association with anionic membrane phospholipids for activity [14] Phosphatidylinositol mannosides stimulate fusion of early endosomes with mycobacterial phagosomes [30] Glycosylated phosphatidylinositol causes phagosome maturation arrest [114] SapM, a mycobacterial derived phosphatase hydrolyses PI3P contributing to inhibition of phagolysosome maturation [115] Sphingosine 1-kinase is recruited to nascent phagosomes [118] Inhibition of sphingolipid biosynthesis in T. gondii blocks replication [119] SP Sphingomyelin metabolism important for P. falciparum development [120] Inhibition of cholesterol biosynthesis inhibits Hepatitis C virus RNA replication [15] Inhibition of cholesterol acquisition by the host lowers T. gondii replication [40] ST Cholesterol esterification essential for optimal T. gondii proliferation [121,122] Isopreonoid synthesis inhibitors with anti-malarial [123] and anti-T. gondii activity [124] PR Block of protein farnesylation as antiapicomplexan therapies [125] 5…”

Therapeutic intervention based on protein prenylation and associated modifications

“…FTIs are cytotoxic to these protozoa, perhaps because they contain PFT but seem to lack PGGT-I (refs. [133][134][135][136] ). In the case of malaria, the target of FTI toxicity is almost certainly PFT, given that parasites that have become resistant to FTIs contain mutant PFTs that bind FTIs less tightly 137 .…”

Prenylation of Saccharomyces cerevisiae Chs4p Affects Chitin Synthase III Activity and Chitin Chain Length

“…In order to decrease the costs associated with de novo drug design and accelerate the development of new chemotherapeutics, FTase inhibitors are currently being investigated as agents for protozoan pathogens (13). Since deletion of the FTase catalytic subunit (RAM1) is lethal in the pathogenic fungus Cryptococcus neoformans, in contrast to the case in Saccharomyces cerevisiae (44), FTase inhibitors may be suitable as antifungal drugs.…”