Protein prenyl transferase activities of Plasmodium falciparum

Chakrabarti, Debopam; Azam, Tania; DELVECCHIO, Cherie; Qiu, Libo; Park, Yong-il; Allen, Charles M.

doi:10.1016/s0166-6851(98)00065-6

Cited by 112 publications

(136 citation statements)

References 49 publications

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“…1). DMAPP then condenses sequentially with three molecules of IPP to form geranyl diphosphate (GPP), farnesyl diphosphate (FPP), and geranylgeranyl diphosphate (GGPP), which is then used to prenylate proteins (26). In addition, in P. falciparum, GGPP is converted via prephytoene diphosphate to phytoene and then to carotenoids (27); plus, the longer-chain diphosphates are converted to quinones such as Men-4 (28) as well as dolichols (29).…”

Section: Resultsmentioning

confidence: 99%

Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity

Dossin

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We report the results of an in vitro screening assay targeting the intraerythrocytic form of the malaria parasite Plasmodium falciparum using a library of 560 prenyl-synthase inhibitors. Based on "growth-rescue" and enzyme-inhibition experiments, geranylgeranyl diphosphate synthase (GGPPS) is shown to be a major target for the most potent leads, BPH-703 and BPH-811, lipophilic analogs of the bone-resorption drugs zoledronate and risedronate. We determined the crystal structures of these inhibitors bound to a Plasmodium GGPPS finding that their head groups bind to the ½Mg 2þ 3 cluster in the active site in a similar manner to that found with their more hydrophilic parents, whereas their hydrophobic tails occupy a long-hydrophobic tunnel spanning both molecules in the dimer. The results of isothermal-titration-calorimetric experiments show that both lipophilic bisphosphonates bind to GGPPS with, on average, a ΔG of −9 kcal mol −1 , only 0.5 kcal mol −1 worse than the parent bisphosphonates, consistent with the observation that conversion to the lipophilic species has only a minor effect on enzyme activity. However, only the lipophilic species are active in cells. We also tested both compounds in mice, finding major decreases in parasitemia and 100% survival. These results are of broad general interest because they indicate that it may be possible to overcome barriers to cell penetration of existing bisphosphonate drugs in this and other systems by simple covalent modification to form lipophilic analogs that retain their enzyme-inhibition activity and are also effective in vitro and in vivo.M alaria, caused by Plasmodium spp., causes approximately 1 million deaths each year (1), and there are ever-present problems due to drug resistance (2). There is, therefore, a need for new drugs and drug leads. In earlier work, we and others found that the bisphosphonate class of drugs (3) used to treat bonerelated diseases-osteoporosis, Paget disease, and hypercalcemia due to malignancy-also inhibited the growth of a range of parasitic protozoa, including Trypanosoma cruzi (4, 5), Trypanosoma brucei (4, 6), Leishmania spp. (4,7,8), Toxoplasma gondii (4, 9), Cryptosporidium parvum (10, 11), Entamoeba histolytica (4, 12, 13), and Plasmodium spp. (4, 13-15). In the case of Plasmodium spp., the most potent inhibitors were not, however, the nitrogencontaining bisphosphonates such as zoledronate or risedronate (Scheme 1) used to treat bone diseases, but more lipophilic n-alkyl bisphosphonates (13). Their target in Plasmodium falciparum was not determined. However, more recently, a Plasmodium vivax geranylgeranyl diphosphate synthase (PvGGPPS) has been cloned, expressed, purified, and crystallized, and its three-dimensional structure determined (16). The enzyme is inhibited by bisphosphonates (16), so it seemed possible that it might be a target for the inhibitors discovered earlier. To investigate this possibility, we recently determined the IC 50 values for 25 bisphosphonates against PvGGPPS and compared the results for enzyme inhi...

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Section: Resultsmentioning

confidence: 99%

Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity

Dossin

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Reduction of benzamide into benzylamine decreases antimalarial activity (15c vs. 19). As previously seen for other series of FTase mammalian inhibitors with potent antimalarial activities, 4,18,19) no correlation can be observed between the two biological activities. The most potent inhibitor of FTase in the series (19) displays the lowest antimalarial activity.…”

Section: Resultsmentioning

confidence: 53%

“…Among them, protein farnesyl transferase (PFT) has been a major target in the conception of new anticancer drugs. 3) In an effort to identify a new and more effective drug target, Chakrabarti 4,5) found that the peptidomimetic L-745,631 (Chart 1) was the best inhibitor of P. falciparum PFT and also a good inhibitor of parasite growth.This finding suggests the real potential of designing or identifying inhibitors of P. falciparum prenyl transferase as an approach to malaria therapy. In addition, several works have reported mammalian PFT inhibitors displaying potent antimalarial activities in vitro and more recently in vivo.…”

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confidence: 99%

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Novel N-(4-Piperidinyl)benzamide Antimalarials with Mammalian Protein Farnesyltransferase Inhibitory Activity

Ryckebusch

Gilleron

Millet

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Antimalarial drugs saved millions of lives during the 20th century. However, owing to the onset of drug resistance, there is now an urgent need to identify new drug targets in Plasmodium falciparum and to develop effective new antimalarial agents. 1,2) Prenylated proteins have been shown to function in important cellular processes including signal transductions. Among them, protein farnesyl transferase (PFT) has been a major target in the conception of new anticancer drugs. 3) In an effort to identify a new and more effective drug target, Chakrabarti 4,5) found that the peptidomimetic L-745,631 (Chart 1) was the best inhibitor of P. falciparum PFT and also a good inhibitor of parasite growth.This finding suggests the real potential of designing or identifying inhibitors of P. falciparum prenyl transferase as an approach to malaria therapy. In addition, several works have reported mammalian PFT inhibitors displaying potent antimalarial activities in vitro and more recently in vivo. 6) Small inhibitors of mammalian FTase developed as anticancer drugs like BMS-214662 [7][8][9][10][11] are also effective inhibitors of P. falciparum growth. 12,13) Results and DiscussionOur work has focused on peptidomimetic inhibitors based on the CA 1 A 2 X tetrapeptide, known to be responsible for interaction with the mammalian FTase, where the A 1 A 2 peptide is replaced by the structurally restricted N-(4-piperidinyl)benzamide scaffold. Initial studies 14) led us to compound 1 which possessed an IC 50 (isolated enzyme FTase) as low as 22.8 nM, but did not inhibit the proliferation of tumor cells in culture (Chart 2). More recently, 15) we synthesized a series of derivatives of compound 1, of general structure 2 which was the outcome of three structural modifications: (i) replacement of methioninate by phenylalaninate or isoleucinate (R 1 ) with the aim of increasing selectivity versus geranylgeranyl transferase, based on our previous results 14) (ii) replacement of the cysteinyl moiety by a known metal chelator, i.e. (1-benzylimidazol-5-yl)methyl substituted in para position (R 2 ) of benzyl in order to increase cellular uptake (iii) reduction of the benzoyl group into benzyl (R 3 ) in order to introduce flexibility into this region of the molecule. Target compounds 15a-c, 16c, 17c, 18 were obtained by reductive amination between adequate imidazolylcarbaldehydes 8a-c and 4-aminopiperidines 12-14. The synthesis of 5-formylimidazoles 8a-c was completed (Chart 3) in 5 steps according to a strategy 16,17) described for the preparation of regiochemically substituted imidazoleacetic esters: tritylation of N 1 -imidazole (4), protection of primary alcohol as ester (5), benzylation of N 3 and detritylation of N 1 (6a-c). The aldehyde function was finally created by chemical oxidation of the hydroxymethyl group (7a-c) resulting from hydrolysis of the ester (6a-c). Piperidines 9-11 were also prepared (Chart 4) from reductive amination of N-Bocpiperidone with adequate a-amino esters. Benzoylation and deprotection of piperidine (compounds 1...

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“…La famille entière des Rab de P. falciparum vient d'être décrite avec dix gènes exprimés dans les érythro-cytes infectés et un gène (Pfrab11b) qui semble spéci-fique d'un autre stade de développement du parasite (voir Tableau II, pour les fonctions potentielles) [26]. Les Rab sont associées aux membranes après prénylation de leur extré-mité carboxyterminale (des di-peptides CXC ou CC) par une enzyme parasitaire [27]. Le recyclage des vésicules d'une membrane donneuse à la membrane accepteuse dépend des protéines Rab dans une conformation liant le GDP, et en association avec un transporteur appelé rabGDI dont le gène correspondant (Pfrabgdi) a été isolé chez le parasite [28].…”

Section: Régulation Du Trafic Protéines Rabunclassified

Trafic protéique dans le globule rouge infecté parPlasmodium

Baunaure

Langsley

2005

Med Sci (Paris)

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Protein prenyl transferase activities of Plasmodium falciparum

Cited by 112 publications

References 49 publications

Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity

Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity

Novel N-(4-Piperidinyl)benzamide Antimalarials with Mammalian Protein Farnesyltransferase Inhibitory Activity

Trafic protéique dans le globule rouge infecté parPlasmodium

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