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Caenorhabditis elegans is a useful model for anthelmintic discovery.

Burns AR, Luciani GM, Musso G, Bagg R, Yeo M, Zhang Y, Rajendran L, Glavin J, Hunter R, Redman E, Stasiuk S, Schertzberg M, Angus McQuibban G, Caffrey CR, Cutler SR, Tyers M, Giaever G, Nislow C, Fraser AG, MacRae CA, Gilleard J, Roy PJ - Nat Commun (2015)

Bottom Line: We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules.We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain.This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

View Article: PubMed Central - PubMed

Affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.

ABSTRACT
Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

No MeSH data available.


Related in: MedlinePlus

Nematode selectivity and structural profiling of the 275 C. elegans-lethal molecules.(a) Heat map indicating the lethality (or lack thereof) induced by each of the 275 C. elegans-lethals in two species of parasitic nematode, as well as zebrafish embryos and human embryonic kidney (HEK) cells. For each species, the number of molecules that induce lethality is indicated to the right of the heat map. The molecules segregate into three groups based on their nematode selectivity and cross-species lethality. If a genetic screen for resistant mutants was performed for a given molecule, this is indicated, as well as the outcome of the screen. (b) Network based on the structural similarity of the 275 C. elegans-lethal molecules. Nodes represent molecules, and edges connect molecules with a pairwise Tanimoto/FP2 score >0.55 (see Methods). The group to which each molecule belongs is indicated by the node fill colour, whereas the genetic screen information is indicated by the node border colour. In the legend, the number of molecules is indicated in parentheses. The 19 clusters containing three or more molecules are named C1 to C19. The wact-11 structural family (cluster C10) is magnified, and the names of each molecule in the family are indicated.
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f2: Nematode selectivity and structural profiling of the 275 C. elegans-lethal molecules.(a) Heat map indicating the lethality (or lack thereof) induced by each of the 275 C. elegans-lethals in two species of parasitic nematode, as well as zebrafish embryos and human embryonic kidney (HEK) cells. For each species, the number of molecules that induce lethality is indicated to the right of the heat map. The molecules segregate into three groups based on their nematode selectivity and cross-species lethality. If a genetic screen for resistant mutants was performed for a given molecule, this is indicated, as well as the outcome of the screen. (b) Network based on the structural similarity of the 275 C. elegans-lethal molecules. Nodes represent molecules, and edges connect molecules with a pairwise Tanimoto/FP2 score >0.55 (see Methods). The group to which each molecule belongs is indicated by the node fill colour, whereas the genetic screen information is indicated by the node border colour. In the legend, the number of molecules is indicated in parentheses. The 19 clusters containing three or more molecules are named C1 to C19. The wact-11 structural family (cluster C10) is magnified, and the names of each molecule in the family are indicated.

Mentions: To further characterize our 275 C. elegans-lethal molecules, we organized them into three separate groups based on their phylogenetic bioactivity profiles (Fig. 2a). Group 1 contains 102 molecules that are lethal to only one or two of the three nematode species tested, but are non-lethal to zebrafish and HEK cells. Group 2 contains 67 compounds that are lethal to all three nematode species, but are non-lethal to zebrafish and human cells. Group 3 contains the remaining 106 compounds that are lethal to fish or HEK cells, and have varied bioactivity in different nematode species. In particular, the 67 molecules in group 2 represent potentially ideal anthelmintic leads; they have activity across multiple nematode species, and appear not to affect vertebrates.


Caenorhabditis elegans is a useful model for anthelmintic discovery.

Burns AR, Luciani GM, Musso G, Bagg R, Yeo M, Zhang Y, Rajendran L, Glavin J, Hunter R, Redman E, Stasiuk S, Schertzberg M, Angus McQuibban G, Caffrey CR, Cutler SR, Tyers M, Giaever G, Nislow C, Fraser AG, MacRae CA, Gilleard J, Roy PJ - Nat Commun (2015)

Nematode selectivity and structural profiling of the 275 C. elegans-lethal molecules.(a) Heat map indicating the lethality (or lack thereof) induced by each of the 275 C. elegans-lethals in two species of parasitic nematode, as well as zebrafish embryos and human embryonic kidney (HEK) cells. For each species, the number of molecules that induce lethality is indicated to the right of the heat map. The molecules segregate into three groups based on their nematode selectivity and cross-species lethality. If a genetic screen for resistant mutants was performed for a given molecule, this is indicated, as well as the outcome of the screen. (b) Network based on the structural similarity of the 275 C. elegans-lethal molecules. Nodes represent molecules, and edges connect molecules with a pairwise Tanimoto/FP2 score >0.55 (see Methods). The group to which each molecule belongs is indicated by the node fill colour, whereas the genetic screen information is indicated by the node border colour. In the legend, the number of molecules is indicated in parentheses. The 19 clusters containing three or more molecules are named C1 to C19. The wact-11 structural family (cluster C10) is magnified, and the names of each molecule in the family are indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4491176&req=5

f2: Nematode selectivity and structural profiling of the 275 C. elegans-lethal molecules.(a) Heat map indicating the lethality (or lack thereof) induced by each of the 275 C. elegans-lethals in two species of parasitic nematode, as well as zebrafish embryos and human embryonic kidney (HEK) cells. For each species, the number of molecules that induce lethality is indicated to the right of the heat map. The molecules segregate into three groups based on their nematode selectivity and cross-species lethality. If a genetic screen for resistant mutants was performed for a given molecule, this is indicated, as well as the outcome of the screen. (b) Network based on the structural similarity of the 275 C. elegans-lethal molecules. Nodes represent molecules, and edges connect molecules with a pairwise Tanimoto/FP2 score >0.55 (see Methods). The group to which each molecule belongs is indicated by the node fill colour, whereas the genetic screen information is indicated by the node border colour. In the legend, the number of molecules is indicated in parentheses. The 19 clusters containing three or more molecules are named C1 to C19. The wact-11 structural family (cluster C10) is magnified, and the names of each molecule in the family are indicated.
Mentions: To further characterize our 275 C. elegans-lethal molecules, we organized them into three separate groups based on their phylogenetic bioactivity profiles (Fig. 2a). Group 1 contains 102 molecules that are lethal to only one or two of the three nematode species tested, but are non-lethal to zebrafish and HEK cells. Group 2 contains 67 compounds that are lethal to all three nematode species, but are non-lethal to zebrafish and human cells. Group 3 contains the remaining 106 compounds that are lethal to fish or HEK cells, and have varied bioactivity in different nematode species. In particular, the 67 molecules in group 2 represent potentially ideal anthelmintic leads; they have activity across multiple nematode species, and appear not to affect vertebrates.

Bottom Line: We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules.We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain.This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

View Article: PubMed Central - PubMed

Affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.

ABSTRACT
Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

No MeSH data available.


Related in: MedlinePlus