Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity

Nallan, Laxman; Bauer, Kevin D.; Bendale, Pravin; Rivas, Kasey; Yokoyama, Kohei; Hornéy, Carolyn P.; Pendyala, Prakash Rao; Floyd, David M.; Lombardo, Louis J.; Williams, David; Hamilton, Andrew D.; Sebti, Saı̈d M.; Windsor, William; Weber, Patricia C; Buckner, Frederick S.; Chakrabarti, Debopam; Gelb, Michael H.; Voorhis, Wesley C. Van

doi:10.1021/jm0491039

Cited by 169 publications

(149 citation statements)

References 26 publications

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“…The tetrahydroquinoline series of FTIs, originally developed by Bristol-Myers Squibb as anticancer agents, are the most promising antimalarial FTIs reported so far. They kill parasites in culture in the low nanomolar range and can cure rodents infected with malaria when dosed orally 138 . This illustrates the 'piggyback medicinal chemistry' approach of taking advantage of work done by large pharmaceutical companies and extending it for use in treating neglected diseases.…”

Section: Ftis As Tropical Parasitic Disease Therapeuticsmentioning

confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

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Section: Ftis As Tropical Parasitic Disease Therapeuticsmentioning

confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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“…The 50 kDa proteins were analyzed and found to be modified by a farnesyl group; the lower molecular mass proteins, however, were found to be geranylgeranylated, presumably after the conversion of farnesol into both farnesyl pyrophosphate and geranylger-anyl pyrophosphate. Our group later showed that the 50 kDa farnesylated proteins, but not the lower molecular mass geranylgeranylated proteins, were specifically inhibited by PFTIs (11). Using synchronized P. falciparum, Chakrabarti et al (5) demonstrated the stage-specific incorporation of prenylation precursors, the highest amount of incorporation occurring in the trophozoite (mid erythrocytic stage) to schizont (cell division stage) and schizont to ring (early erythrocytic stage) transition states in the erythrocytic life cycle of the parasite.…”

Section: Pft In Pathogenic Protozoamentioning

confidence: 96%

“…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)(11)(12)(13).…”

mentioning

confidence: 99%

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

Eastman

Buckner

Yokoyama

et al. 2006

Journal of Lipid Research

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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...

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“…T. brucei and malaria parasites show high sensitivity to inhibition of PFT compared to mammalian cells [20][21][22][23]. We previously reported that potent PFT inhibitors are highly effective in blocking growth of malaria parasites and T. brucei bloodstream forms, suggesting the opportunity to develop PFT inhibitors as therapeutics for diseases caused by these parasites [22][23][24][25]. It is likely that PFT inhibitors are selectively toxic to these protozoan parasites because of absence of PGGT-I or lack of alternative modification of critical farnesylated proteins in the parasites.…”

Section: Introductionmentioning

confidence: 99%

Protein geranylgeranyltransferase-I of Trypanosoma cruzi

Yokoyama

Gillespie

Voorhis

et al. 2008

Molecular and Biochemical Parasitology

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Protein geranylgeranyltransferase type I (PGGT-I) and protein farnesyltransferase (PFT) occur in many eukaryotic cells. Both consist of two subunits, the common αsubunit and a distinct β subunit. In the gene database of protozoa Trypanosoma cruzi, the causative agent of Chagas' disease, a putative protein that consists of 401 amino acids with ∼20% amino acid sequence identity to the PGGT-I β of other species was identified, cloned, and characterized. Multiple sequence alignments show that the T. cruzi ortholog contains all three of the zinc-binding residues and several residues uniquely conserved in the β subunit of PGGT-I. Co-expression of this protein and the α subunit of T. cruzi PFT in Sf9 insect cells yielded a dimeric protein that forms a tight complex selectively with [ 3 H] geranylgeranyl pyrophosphate, indicating a key characteristic of a functional PGGT-I. Recombinant T. cruzi PGGT-I ortholog showed geranylgeranyltransferase activity with distinct specificity toward the C-terminal CaaX motif of protein substrates compared to that of the mammalian PGGT-I and T. cruzi PFT. Most of the CaaX-containing proteins with X=Leu are good substrates of T. cruzi PGGT-I, and those with X=Met are substrates for both T. cruzi PFT and PGGT-I, whereas unlike mammalian PGGT-I, those with X=Phe are poor substrates for T. cruzi PGGT-I. Several candidates for T. cruzi PGGT-I or PFT substrates containing the C-terminal CaaX motif are found in the T. cruzi gene database. Among five C-terminal peptides of those tested, a peptide of a Ras-like protein ending with CVLL was selectively geranylgeranylated by T. cruzi PGGT-I. Other peptides with CTQQ (Tcj2 DNAJ protein), CAVM (TcPRL-1 protein tyrosine phosphatase), CHFM (a small GTPase like protein), and CQLF (TcRho1 GTPase) were specific substrates for T. cruzi PFT but not for PGGT-I. The mRNA and protein of the T. cruzi PGGT-I β ortholog were detected in three life-cycle stages of T. cruzi. Cytosol fractions from trypomastigotes (infectious mammalian stage) and epimastigotes (insect stage) were shown to contain levels of PGGT-I activity that are ∼100-fold lower than PFT activity. The CaaX mimetics known as PGGT-I inhibitors show very low potency against T. cruzi PGGT-I compared to the mammalian enzyme, suggesting the potential to develop selective inhibitors against the parasite enzyme.

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Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity

Cited by 169 publications

References 26 publications

Therapeutic intervention based on protein prenylation and associated modifications

Therapeutic intervention based on protein prenylation and associated modifications

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

Protein geranylgeranyltransferase-I of Trypanosoma cruzi

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