A new class of anthelmintics effective against drug-resistant nematodes

Kaminsky, Ronald; Ducray, Pierre; Jung, Martin; Clover, Ralph; Rufener, Lucien; Bouvier, Jacques; Weber, Sandra; Wenger, Andre; Wieland-Berghausen, Susanne; Goebel, Thomas; Gauvry, Noe͏̈lle; Pautrat, François; Skripsky, Thomas; Froelich, Olivier; Komoin-Oka, C.; Westlund, Bethany; Sluder, Ann E.; Mäser, Pascal

doi:10.1038/nature06722

Cited by 455 publications

(436 citation statements)

References 22 publications

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“…Equally, the range of receptor and channel proteins identified here are interesting because many common anthelmintics bind such targets 19 . Here, we predicted 279 G protein-coupled receptors (GPCRs) for A. suum and 477 channel or pore proteins (Supplementary Data 4), including 272 voltage-gated and 98 ligand-gated ion channels.…”

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confidence: 99%

“…Here, we predicted 279 G protein-coupled receptors (GPCRs) for A. suum and 477 channel or pore proteins (Supplementary Data 4), including 272 voltage-gated and 98 ligand-gated ion channels. Many voltage-gated ion channels are known targets for nematocidal drugs, such as macrocyclic lactones (for example, ivermectin) and levamisole, and an aminoacetonitrile derivative, monepantel, is the most recent example of a highly effective nematocide that binds to a ligand-gated ion channel 19 . Importantly, in the A. suum gene set, we found a homologue (acr-23) of the C. elegans monepantel receptor 19 , suggesting that this drug may kill A. suum.…”

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confidence: 99%

“…Many voltage-gated ion channels are known targets for nematocidal drugs, such as macrocyclic lactones (for example, ivermectin) and levamisole, and an aminoacetonitrile derivative, monepantel, is the most recent example of a highly effective nematocide that binds to a ligand-gated ion channel 19 . Importantly, in the A. suum gene set, we found a homologue (acr-23) of the C. elegans monepantel receptor 19 , suggesting that this drug may kill A. suum. In addition, we detected 462 transporters (for example, small molecule porter proteins), of which the major facilitator (n 5 155), cation symporter (n 5 71) and resistance-nodulation-cell division (n 5 56) superfamilies were most abundant (Supplementary Data 4).…”

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Ascaris suum draft genome

Jex

Liu

et al. 2011

Nature

248

266

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Parasitic diseases have a devastating, long-term impact on human health, welfare and food production worldwide. More than two billion people are infected with geohelminths, including the roundworms Ascaris (common roundworm), Necator and Ancylostoma (hookworms), and Trichuris (whipworm), mainly in developing or impoverished nations of Asia, Africa and Latin America(1). In humans, the diseases caused by these parasites result in about 135,000 deaths annually, with a global burden comparable with that of malaria or tuberculosis in disability-adjusted life years(1). Ascaris alone infects around 1.2 billion people and, in children, causes nutritional deficiency, impaired physical and cognitive development and, in severe cases, death(2). Ascaris also causes major production losses in pigs owing to reduced growth, failure to thrive and mortality(2). The Ascaris-swine model makes it possible to study the parasite, its relationship with the host, and ascariasis at the molecular level. To enable such molecular studies, we report the 273 mega-base draft genome of Ascaris suum and compare it with other nematode genomes. This genome has low repeat content (4.4%) and encodes about 18,500 protein-coding genes. Notably, the A. suum secretome (about 750 molecules) is rich in peptidases linked to the penetration and degradation of host tissues, and an assemblage of molecules likely to modulate or evade host immune responses. This genome provides a comprehensive resource to the scientific community and underpins the development of new and urgently needed interventions (drugs, vaccines and diagnostic tests) against ascariasis and other nematodiases

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Ascaris suum draft genome

Jex

Liu

et al. 2011

Nature

248

266

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“…The frequent use (and misuse) of APs has also resulted in the emergence of resistant populations of endo-and ectoparasites (CHAGAS et al, 2008;GRAF et al, 2004;KAMINSKY et al, 2008;BARROS et al, 2012). For these reasons, as well as due to their lower cost, the absence of residues in meat and milk, their low environmental impact, their ease of use as food additives, the use of homeopathic and herbal medicines as APs is significantly increasing in Brazil.…”

Section: Introductionmentioning

confidence: 99%

Weight gain and control of endo- and ectoparasites of beef heifers treated with allopathic, herbal and homeopathic drugs

Catto

Bianchin

Feijó

et al. 2013

Rev. Bras. Parasitol. Vet.

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The aim of this study was to evaluate the efficacy of herbal, homeopathic and allopathic treatments for parasites in beef heifers during two experimental cycles of 318 and 313 days. Treatments: NC -negative control (untreated); HH -treated with homeopathic preparation Homeo bovis Parasitário  ; PC -(positive control) -treated with 10% moxidectina  and an acaricide formulation of cypermethrin, chlorpyrifos and piperonyl butoxide  ; HF -treated with homeopathic preparation Fator C&MC  ; and FN -treated with neem cake (torta de neem  ) and with neem oil (óleo de neem  ). Parasite egg count (EPG), horn fly (Haematobia irritans) and tick (Rhipicephalus (Boophilus) microplus) assessment and animal weighting were performed at 28-day intervals. Blood samples were collected at the first cycle to assess the immune response. Horn fly infestation was not affected by any treatment (P>0.05). The mean number of ticks, which was low in both cycles, was lower (P<0.05) in the first cycle in animals that received PC treatment. In both experimental cycles, the mean EPG of the PC-treated animals was lower (P<0.05) than the animals receiving other treatments. Treatments had no effect on the immune response (P>0.05). The animals treated with allopathic drugs were 22 to 30 kg heavier (P<0.05) than untreated animals or animals treated with alternative drugs.Keywords: Beef cattle, tick, nematodes, horn fly, anthelmintics, alternative control. ResumoO objetivo do trabalho foi avaliar a eficácia de tratamentos fitoterápicos, homeopáticos e alopáticos contra ecto e endoparasitas na recria de novilhas, em dois ciclos experimentais subsequentes de 318 e 313 dias. Tratamentos: CN -controle negativo -não tratado; tratamento HH -tratado com homeopático Homeo bovis Parasitário  ; tratamento CP -controle positivo -tratado com moxidectina 10%  e uma formulação acaricida contendo cypermetrina, clorpirifós e butóxido de piperonila  ; tratamento HF -tratado com homeopático Fator C&MC  e tratamento FN -tratados com torta de neem  e com óleo de neem  . A contagem de ovos nas fezes (OPG), a infestação por Haematobia irritans, Rhipicephalus (Boophilus) microplus e pesagem dos animais foram realizadas em intervalos de 28 dias. No primeiro ciclo foi coletado sangue para avaliar a resposta imume. A infestação por mosca-dos-chifres não foi influenciada por nenhum dos tratamentos (P>0,05). Nos dois ciclos o número médio de carrapatos foi baixo e apenas no primeiro foi menor (P>0.05) no tratamento CP em relação aos demais. A média de OPG no tratamento CP foi mais baixa que nos demais tratamentos nos dois ciclos experimentais (P<0,05). Não houve efeito de tratamentos na resposta imune. Os animais do tratamento CP ganharam entre 22 a 30 kg de peso vivo a mais (P<0,05) que os não tratados ou tratados com medicamentos alternativos.

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“…As anthelmintic resistance has become very widespread in H. contortus and related worms (Wolstenholme et al, 2004;Kaplan and Vidyashankar, 2012;Wolstenholme and Martin, 2014), there is an ongoing need for the development of new compounds (cf. von SamsonHimmelstjerna et al, 2005;Kaminsky et al, 2008;Little et al, 2011). Identifying new intervention targets has been challenging, particularly because of a limited understanding of the molecular biology of H. contortus and how it interacts with its host (Nikolaou and Gasser, 2006).…”

Section: Introductionmentioning

confidence: 99%

The barber's pole worm CAP protein superfamily — A basis for fundamental discovery and biotechnology advances

Mohandas

Young

Jabbar

et al. 2015

Biotechnology Advances

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Parasitic worm proteins that belong to the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 (CAP) superfamily are proposed to play key roles in the infection process and the modulation of immune responses in host animals. However, there is limited information on these proteins for most socio-economically important worms. Here, we review the CAP protein superfamily of Haemonchus contortus (barber's pole worm), a highly significant parasitic roundworm (order Strongylida) of small ruminants. To do this, we mined genome and transcriptomic datasets, predicted and curated full-length amino acid sequences (n = 45), undertook systematic phylogenetic analyses of these data and investigated transcription throughout the life cycle of H. contortus. We inferred functions for selected C. elegans orthologs (including vap-1, vap-2, scl-5 and lon-1) based on genetic networking and by integrating data and published information, and were able to infer that a subset of orthologs and their interaction partners play pivotal roles in growth and development via the insulin-like and/or the TGF-beta signaling pathways. The identification of the important and conserved growth regulator LON-1 led us to appraise the threedimensional structure of this CAP protein by comparative modelling. This model revealed the presence of different topological moieties on the canonical fold of the CAP domain, which coincide with an overall charge separation as indicated by the electrostatic surface potential map. These observations suggest the existence of separate sites for effector binding and receptor interactions, and thus support the proposal that these worm molecules act in similar ways as venoms act as ligands for chemokine receptors or G protein-coupled receptor effectors. In conclusion, this review should guide future molecular studies of these molecules, and could support the development of novel interventions against haemonchosis.

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A new class of anthelmintics effective against drug-resistant nematodes

Cited by 455 publications

References 22 publications

Ascaris suum draft genome

Ascaris suum draft genome

Weight gain and control of endo- and ectoparasites of beef heifers treated with allopathic, herbal and homeopathic drugs

The barber's pole worm CAP protein superfamily — A basis for fundamental discovery and biotechnology advances

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