Are Ca2+ channels targets of praziquantel action?

Greenberg, Robert M.

doi:10.1016/j.ijpara.2004.09.004

Cited by 143 publications

(118 citation statements)

References 94 publications

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“…It is hypothesized to act directly or indirectly on calcium channel β (Ca v β) subunits in schstosomes 37 . Given that humans, mice, rats and rabbits can accommodate high quantities of praziquantel with only mild side effects 38 , putative sites related to praziquantel sensitivity in worms may be located in conserved functional domains that have different sequences than in the mammalian hosts.…”

Section: New Intervention Targetsmentioning

confidence: 99%

“…The BID domain has been suggested to be the region whereby the Ca v β and Ca v α subunits interact 39 . Additionally, two non-functional putative serine phosphorylation sites in this region of wild-type SmCa v β 1 have been linked to praziquantel action, as mutations affecting either of the two wild-type sites result in the elimination of sensitivity 37 . Phylogenetic analysis confirmed in detail the previous suggestion that the E. granulosus Ca v β 1 proteins are encoded by different orthologs, whereas Ca v β 2 and the host Ca v β proteins represent one orthologous group (Fig.…”

Section: New Intervention Targetsmentioning

confidence: 99%

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The genome of the hydatid tapeworm Echinococcus granulosus

et al. 2013

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A r t i c l e sThe dog tapeworm E. granulosus is one of a group of medically important parasitic helminths of the family Taeniidae (Platyhelminthes; Cestoda; Cyclophyllidea) that infect at least 50 million people globally 1 . Its life cycle involves two mammals, including an intermediate host, usually a domestic or wild ungulate (humans are accidental intermediate hosts) and a canine-definitive host, such as the domestic dog. The larval (metacestode) stage causes hydatidosis (cystic hydatid disease; cystic echinococcosis), a chronic cyst-forming disease in the intermediate (human) host. Currently, up to 3 million people are infected with E. granulosus 2,3 , and, in some areas, 10% of the population has detectable hydatid cysts by abdominal ultrasound and chest X-ray 4,5 .E. granulosus has no gut, circulatory or respiratory organs. It is monoecious, producing diploid eggs that give rise to ovoid embryos, the oncospheres. Strobilization is a notable feature of cestode biology, whereby proglottids bud distally from the anterior scolex, resulting in the production of tandem reproductive units exhibiting increasing degrees of development. A unique characteristic of the larvae (protoscoleces, PSCs) within the hydatid cyst is an ability to develop bidirectionally into an adult worm in the dog gastrointestinal tract or into a secondary hydatid cyst in the intermediate (human) host, a process triggered by bile acids 6 . Another distinct feature of E. granulosus is its capacity to infect and adapt to a large number of mammalian species as intermediate hosts, which has contributed to its cosmopolitan global distribution.Here we report the sequence and analysis of the E. granulosus genome. Comprising nine pairs of chromosomes 7 , it is one of the first cestode genomes to be sequenced and complements the recent publication by Tsai et al. 8 of a high-quality genome for Echinococcus multilocularis (the cause of alveolar echinococcosis), together with draft genomes of three other tapeworm species including E. granulosus. Our study provides insights into the biology, development, differentiation, evolution and host interaction of E. granulosus and has identified a range of drug and vaccine targets that can facilitate the development of new intervention tools for hydatid treatment and control. Cystic echinococcosis (hydatid disease), caused by the tapeworm E. granulosus, is responsible for considerable human morbidity and mortality. This cosmopolitan disease is difficult to diagnose, treat and control. We present a draft genomic sequence for the worm comprising 151.6 Mb encoding 11,325 genes. Comparisons with the genome sequences from other taxa show that E. granulosus has acquired a spectrum of genes, including the EgAgB family, whose products are secreted by the parasite to interact and redirect host immune responses. We also find that genes in bile salt pathways may control the bidirectional development of E. granulosus, and sequence differences in the calcium channel subunit EgCa v b 1 may be associated with praziquantel sens...

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Section: New Intervention Targetsmentioning

confidence: 99%

Section: New Intervention Targetsmentioning

confidence: 99%

The genome of the hydatid tapeworm Echinococcus granulosus

et al. 2013

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“…PZQ causes 2 major effects on flatworms by disruption of Ca 2+ homeostasis; a rapid, sustained muscular contraction and tegumental disruption of flatworms (Greenberg, 2005). Major changes in PZQ-treated trematodes are vacuolization of the tegument and subtegumental parenchymal layers, and narrowing of the intestinal lumens (Seo et al, 1985).…”

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confidence: 99%

Collection of Clonorchis sinensis adult worms from infected humans after praziquantel treatment

et al. 2007

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“…The drug is only effective against adult or pre-adult forms (Greenberg, 2005). Furthermore, praziquantel confers no protection against subsequent infection and people may become reinfected within days of treatment (Ross et al, 2002).…”

Section: Treatments For Schistosomiasis -Drugsmentioning

confidence: 99%

“…This drug has been used in mass treatment campaigns in many countries and remains a primary tool in the war against the disease (Knopp et al, 2013). The mode of action of praziquantel remains unknown, although recent developments strongly suggest a role for the drug in calcium homeostasis in the parasites and notably in calcium transport complexes (Greenberg, 2005;You et al, 2013). The drug remains highly effective for a wide range of flatworm diseases of humans and domestic animals.…”

Section: Treatments For Schistosomiasis -Drugsmentioning

confidence: 99%

Structure–function analysis of apical membrane‐associated molecules of the tegument of schistosome parasites of humans: prospects for identification of novel targets for parasite control

Leow

Willis

Hofmann

et al. 2014

British J Pharmacology

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Neglected tropical diseases are a group of some 17 diseases that afflict poor and predominantly rural people in developing nations. One significant disease that contributes to substantial morbidity in endemic areas is schistosomiasis, caused by infection with one of five species of blood fluke belonging to the trematode genus Schistosoma. Although there is one drug available for treatment of affected individuals in clinics, or for mass administration in endemic regions, there is a need for new therapies. A prominent target organ of schistosomes, either for drug or vaccine development, is the peculiar epithelial syncytium that forms the body wall (tegument) of this parasite. This dynamic layer is maintained and organized by concerted activity of a range of proteins, among which are the abundant tegumentary annexins. In this review, we will outline advances in structure-function analyses of these annexins, as a means to understanding tegument cell biology in host-parasite interaction and their potential exploitation as targets for anti-schistosomiasis therapies. LINKED ARTICLESThis article is part of a themed section on Annexins VII Programme. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-7 Abbreviations Anx, annexin; NTDs, neglected tropical diseases; RA, radiation attenuated; Sm, Schistosoma mansoni; TEMs, tetraspanin-enriched microdomains; TSP, tetraspanin Neglected tropical diseases (NTDs)NTDs include some 17 lesser known chronic infections that affect poor and disenfranchised people, primarily, but not exclusively, in developing nations (Hotez et al., 2007;Hotez and Fenwick, 2009). Chronic infections caused by NTDs lead to many adverse outcomes in affected populations and contribute substantially to human morbidity. In addition to microbial and protozoan diseases, NTDs include a number of helminth infections, such as diseases caused by flatworm parasites, notably schistosomiasis, echinococcosis and liver fluke diseases, as well as roundworm parasites, such as the major soil transmitted helminth infections (ascariasis, trichuriasis and hookworm diseases). Although no individual NTD rivals the major infectious threats of HIV, malaria or tuberculosis in terms of global impact of disease, collectively, the NTDs contribute substantially to morbidity throughout the world (Engels and Savioli, 2006). A number of factors present major challenges for the development of new treatments for NTDs. Firstly, NTDs are chronic diseases, which may reside in affected people as lifelong infections. Secondly, NTDs are not always associated with human mortality and the burden of these diseases can be subtle, hidden among such other measures of disease burden as hindered development, poor cognitive function and chronic ailments. Thirdly, as stated, NTDs often affect the poorest of the poor, people often unable to pay for medical treatments, especially for chronic illnesses. Hence, these diseases receive less attention than other, immediately lifethreatening infectious diseases. La...

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Are Ca2+ channels targets of praziquantel action?

Cited by 143 publications

References 94 publications

The genome of the hydatid tapeworm Echinococcus granulosus

The genome of the hydatid tapeworm Echinococcus granulosus

Collection of Clonorchis sinensis adult worms from infected humans after praziquantel treatment

Structure–function analysis of apical membrane‐associated molecules of the tegument of schistosome parasites of humans: prospects for identification of novel targets for parasite control

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