Lipophilic Bisphosphonates Are Potent Inhibitors of
            <i>Plasmodium</i>
            Liver-Stage Growth

Singh, Agam Prasad; Zhang, Yonghui; No, Joo Hwan; Docampo, Roberto; Nussenzweig, Victor; Oldfield, Eric

doi:10.1128/aac.00198-10

Cited by 58 publications

(58 citation statements)

References 21 publications

(27 reference statements)

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“…S5A, it can be seen that this molecule can be thought of as being derived from a "fusion" of the key structural features found in zoledronate (the bisphosphonate and imidazole group) with the hydrophilic diphosphate and lipophilic features found in FPP or GGPP. In previous work, we found that the lipophilic pyridinium bisphosphonate BPH-715 (Scheme 1) was a potent inhibitor of both liver-stage as well as blood-stage malaria parasites (14), but BPH-703 is far less active than is BPH-715 against three human cell lines (approximately 133 μM vs. approximately 168 nM for BPH-715; Table S1). In the case of BPH-811, it can again be seen (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This is, of course, a desirable feature of a bone drug but not of an antiinfective-drug lead; and in recent work, we have been developing a class of compounds called "lipophilic bisphosphonates" (20,21) in which the 1-OH group on the bisphosphonate backbone, part of the tridentate "bone-hook," is removed and in which a variety of hydrophobic side chains are attached to the molecules to increase logP values, typically from approximately −2 or −3 to approximately 2 or 3. These lipophilic bisphosphonates have far more potent activity both in vitro and in vivo than do conventional bisphosphonates in tumor cell-growth inhibition and γδ T-cell-activation assays (20, 21) as well as against malaria parasites (14). In this work, we elected to screen our in-house library of 560 prenyl-synthase inhibitors, developed over the past decade as anticancer drug leads and as antibacterials (20)(21)(22)(23)(24), for their activity in P. falciparum growth inhibition inside red cells.…”

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confidence: 99%

“…(4,7,8), Toxoplasma gondii (4, 9), Cryptosporidium parvum (10,11), Entamoeba histolytica (4,12,13), and Plasmodium spp. (4,(13)(14)(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).…”

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confidence: 99%

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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%

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confidence: 99%

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confidence: 99%

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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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“…The sporozoite development within the hepatocyte into a schizont stage is followed either by Giemsa staining or immunofluorescence assay using specific antibodies or a genetically-manipulated fluorescent parasite. Potential antimalarial drugs acting on the hepatic stage have emerged (Carraz et al, 2006, Mahmoudi et al, 2003, Mahmoudi et al, 2008, Parvanova et al, 2009, Singh et al, 2010, Tasdemir et al, 2010, Yu et al, 2008. A high-throughput in vitro screening of drug activity on Plasmodium liver stages was developed based on a sophisticated infrared fluorescence scanning system, which allows rapid, automatic counting of infected hepatocytes (Gego et al, 2006).…”

Section: Bioassays For the Hepatic Stage Of Plasmodiummentioning

confidence: 99%

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

Grellier¹,

Deregnaucourt²,

Isabelle³

2012

Malaria Parasites

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“…The in vivo antimalarial activity of T-2307 against the liver stage was assessed by evaluating a prepatent period for the blood stage parasites in the mice after the sporozoite inoculation (11). Sporozoites were isolated from the salivary glands of P. bergheiinfected Anopheles stephensi mosquitoes.…”

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In Vitro and In Vivo Antimalarial Activities of T-2307, a Novel Arylamidine

Kimura

Nishikawa

Nomura

et al. 2012

Antimicrob Agents Chemother

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bT-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated the in vitro and in vivo antimalarial activity of T-2307. The 50% inhibitory concentrations (IC 50 s) of T-2307 against Plasmodium falciparum FCR-3 and K-1 strains were 0.47 and 0.17 M, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibited in vitro and in vivo antimalarial activity. M alaria, caused by protozoan parasites of the genus Plasmodium, is one of the world's leading killer infectious diseases. There are an estimated 200 to 300 million new cases of the disease each year worldwide, and 0.8 to 1 million deaths (5, 15). Many of these deaths occur in children and are the result of severe and cerebral malaria caused by Plasmodium falciparum, the most pathogenic of the four species that infect humans (5).In the absence of a vaccine for malaria and in view of widespread resistance of the parasites to antimalarial drugs in current use, new agents are urgently needed to combat malaria (4).We had previously reported that T-2307, a novel arylamidine, exhibits broad-spectrum in vitro and in vivo antifungal activity against clinically significant pathogens (7, 8, 16). The analogous arylamidine derivatives, such as pentamidine and DB75, exhibit antiprotozoan activities against Plasmodium, Trypanosoma, and Leishmania (2,3,14). Accordingly, T-2307, similar to pentamidine and DB75, is expected to exhibit antiprotozoan activity. In the present study, we investigated the in vitro and in vivo antimalarial activity of T-2307.The in vitro antimalarial activity of T-2307 against P. falciparum was examined. Parasite cultures were maintained in human erythrocytes suspended at 5% hematocrit in RPMI 1640 containing 0.5% AlbuMAX I solution and 5.95 g of HEPES, 2 g of NaHCO 3 , 0.5 g of L-glutamine, and 50 mg of hypoxanthine per liter. After the parasites had been synchronized to the ring stage by sorbitol lysis (6), T-2307 and reference agents were added to the synchronized parasite culture (ring stage, Ͼ90%, and parasitemia, 0.5%) in a 96-well plate. The plate was incubated for one intraerythrocytic life cycle (FCR-3, 40 h, and K-1, 48 h) at 37°C under a gas mixture of 5% O 2 and 5% CO 2 . In order to assess parasite growth, lysis buffer containing 0.02% SYBR green I was added to the parasite culture, and after incubation for 1 h, fluorescence was measured at excitation and emission wavelengths of 485 and 535 nm, respectively (12). The 50% inhibitory concentrations (IC 50 s) of T-2307 and the reference agents against the chloroquine-sensitive P. falciparum FCR-3 strain and the chloroquine-resistant P. falciparum K-1 strain are shown in Table 1. The IC 50 s of T-2307 against FCR-3 and K-1 strains were 0.47 and 0.17 M, respectively, indicating that T-2307 exhibited no cross-resistance against chloroquine.The stage-specific activities of T-2307 and pentami...

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Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth

Cited by 58 publications

References 21 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

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

In Vitro and In Vivo Antimalarial Activities of T-2307, a Novel Arylamidine

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