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Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth.

ABSTRACT: Nitrogen-containing bisphosphonates, drugs used to treat bone resorption diseases, also have activity against a broad range of protists, including blood-stage Plasmodium spp. Here, we show that new-generation "lipophilic" bisphosphonates designed as anticancer agents that block protein prenylation also have potent activity against Plasmodium liver stages, with a high (>100) therapeutic index. Treatment of mice with the bisphosphonate BPH-715 and challenge with Plasmodium berghei sporozoites revealed complete protection (no blood-stage parasites after 28 days). There was also activity against blood-stage forms in vitro and a 4-day delay in the prepatent period in vivo. The lipophilic bisphosphonates have activity against a Plasmodium geranylgeranyl diphosphate synthase (GGPPS), as well as low nM activity against human farnesyl and geranylgeranyl diphosphate synthases. The most active inhibitor in vitro and in vivo had enzyme inhibitory activity similar to that of the other, less active compounds but was more lipophilic. Lipophilic bisphosphonates are thus promising leads for novel antimalarials that target liver-stage infection.

SUBMITTER: Singh AP

PROVIDER: S-EPMC2897311 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth.

Singh Agam Prasad AP Zhang Yonghui Y No Joo-Hwan JH Docampo Roberto R Nussenzweig Victor V Oldfield Eric E

Antimicrobial agents and chemotherapy 20100510 7

Nitrogen-containing bisphosphonates, drugs used to treat bone resorption diseases, also have activity against a broad range of protists, including blood-stage Plasmodium spp. Here, we show that new-generation "lipophilic" bisphosphonates designed as anticancer agents that block protein prenylation also have potent activity against Plasmodium liver stages, with a high (>100) therapeutic index. Treatment of mice with the bisphosphonate BPH-715 and challenge with Plasmodium berghei sporozoites reve ...[more]

PMID: 20457823

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Project description:Cryptosporidium parvum and Cryptosporidium hominis have emerged as major enteric pathogens of infants in the developing world, in addition to their known importance in immunocompromised adults. Although there has been recent progress in identifying new small molecules that inhibit Cryptosporidium sp. growth in vitro or in animal models, we lack information about their mechanism of action, potency across the life cycle, and cidal versus static activities. Here, we explored four potent classes of compounds that include inhibitors that likely target phosphatidylinositol 4 kinase (PI4K), phenylalanine-tRNA synthetase (PheRS), and several potent inhibitors with unknown mechanisms of action. We utilized monoclonal antibodies and gene expression probes for staging life cycle development to define the timing of when inhibitors were active during the life cycle of Cryptosporidium parvum grown in vitro These different classes of inhibitors targeted different stages of the life cycle, including compounds that blocked replication (PheRS inhibitors), prevented the segmentation of daughter cells and thus blocked egress (PI4K inhibitors), or affected sexual-stage development (a piperazine compound of unknown mechanism). Long-term cultivation of C. parvum in epithelial cell monolayers derived from intestinal stem cells was used to distinguish between cidal and static activities based on the ability of parasites to recover from treatment. Collectively, these approaches should aid in identifying mechanisms of action and for designing in vivo efficacy studies based on time-dependent concentrations needed to achieve cidal activity.IMPORTANCE Currently, nitazoxanide is the only FDA-approved treatment for cryptosporidiosis; unfortunately, it is ineffective in immunocompromised patients, has varied efficacy in immunocompetent individuals, and is not approved in infants under 1?year of age. Identifying new inhibitors for the treatment of cryptosporidiosis requires standardized and quantifiable in vitro assays for assessing potency, selectivity, timing of activity, and reversibility. Here, we provide new protocols for defining which stages of the life cycle are susceptible to four highly active compound classes that likely inhibit different targets in the parasite. We also utilize a newly developed long-term culture system to define assays for monitoring reversibility as a means of defining cidal activity as a function of concentration and time of treatment. These assays should provide valuable in vitro parameters to establish conditions for efficacious in vivo treatment.

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Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth.

Publications

Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth.

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