Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus

Sarah Preston, Junjie Luo, Yuezhou Zhang, Abdul Jabbar, Simon Crawford, Jonathan Baell, Andreas Hofmann, Min Hu, Hai-Bing Zhou, Robin B. Gasser

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Parasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites. Methods: Here, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber's pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system. Results: We identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3-25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds). Conclusion: The potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.

Original languageEnglish
Article number346
Number of pages11
JournalParasites and Vectors
Volume9
Issue number1
DOIs
Publication statusPublished - 16 Jun 2016

Keywords

  • Haemonchus contortus
  • Inhibitory activity
  • Nematode
  • Selective estrogen receptor modulators (SERMs)
  • Selenophene and thiophene-core SERMs

Cite this

Preston, Sarah ; Luo, Junjie ; Zhang, Yuezhou ; Jabbar, Abdul ; Crawford, Simon ; Baell, Jonathan ; Hofmann, Andreas ; Hu, Min ; Zhou, Hai-Bing ; Gasser, Robin B. / Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus. In: Parasites and Vectors. 2016 ; Vol. 9, No. 1.
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abstract = "Background: Parasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites. Methods: Here, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber's pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system. Results: We identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3-25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds). Conclusion: The potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.",
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Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus. / Preston, Sarah; Luo, Junjie; Zhang, Yuezhou; Jabbar, Abdul; Crawford, Simon; Baell, Jonathan; Hofmann, Andreas; Hu, Min; Zhou, Hai-Bing; Gasser, Robin B.

In: Parasites and Vectors, Vol. 9, No. 1, 346, 16.06.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus

AU - Preston, Sarah

AU - Luo, Junjie

AU - Zhang, Yuezhou

AU - Jabbar, Abdul

AU - Crawford, Simon

AU - Baell, Jonathan

AU - Hofmann, Andreas

AU - Hu, Min

AU - Zhou, Hai-Bing

AU - Gasser, Robin B.

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N2 - Background: Parasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites. Methods: Here, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber's pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system. Results: We identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3-25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds). Conclusion: The potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.

AB - Background: Parasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites. Methods: Here, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber's pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system. Results: We identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3-25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds). Conclusion: The potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.

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