Low cost whole-organism screening of compounds for anthelmintic activity

Sarah Preston, Abdul Jabbar, Cameron J Nowell, Anja Joachim, Barbel Ruttkowski, Jonathan Bayldon Baell, Tony Cardno, Pasi K Korhonen, David Michael Piedrafita, Brendan R E Ansell, Aaron R Jex, Andreas Hofmann, Robin Beat Gasser

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber s pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-a]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47?M. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships.
Original languageEnglish
Pages (from-to)333 - 343
Number of pages11
JournalInternational Journal for Parasitology
Volume45
Issue number5
DOIs
Publication statusPublished - 2015

Cite this

Preston, Sarah ; Jabbar, Abdul ; Nowell, Cameron J ; Joachim, Anja ; Ruttkowski, Barbel ; Baell, Jonathan Bayldon ; Cardno, Tony ; Korhonen, Pasi K ; Piedrafita, David Michael ; Ansell, Brendan R E ; Jex, Aaron R ; Hofmann, Andreas ; Gasser, Robin Beat. / Low cost whole-organism screening of compounds for anthelmintic activity. In: International Journal for Parasitology. 2015 ; Vol. 45, No. 5. pp. 333 - 343.
@article{58dd7f3558724be2b71aaf3dbcfe6c47,
title = "Low cost whole-organism screening of compounds for anthelmintic activity",
abstract = "Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber s pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-a]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47?M. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships.",
author = "Sarah Preston and Abdul Jabbar and Nowell, {Cameron J} and Anja Joachim and Barbel Ruttkowski and Baell, {Jonathan Bayldon} and Tony Cardno and Korhonen, {Pasi K} and Piedrafita, {David Michael} and Ansell, {Brendan R E} and Jex, {Aaron R} and Andreas Hofmann and Gasser, {Robin Beat}",
year = "2015",
doi = "10.1016/j.ijpara.2015.01.007",
language = "English",
volume = "45",
pages = "333 -- 343",
journal = "International Journal for Parasitology",
issn = "0020-7519",
publisher = "Elsevier",
number = "5",

}

Preston, S, Jabbar, A, Nowell, CJ, Joachim, A, Ruttkowski, B, Baell, JB, Cardno, T, Korhonen, PK, Piedrafita, DM, Ansell, BRE, Jex, AR, Hofmann, A & Gasser, RB 2015, 'Low cost whole-organism screening of compounds for anthelmintic activity' International Journal for Parasitology, vol. 45, no. 5, pp. 333 - 343. https://doi.org/10.1016/j.ijpara.2015.01.007

Low cost whole-organism screening of compounds for anthelmintic activity. / Preston, Sarah; Jabbar, Abdul; Nowell, Cameron J; Joachim, Anja; Ruttkowski, Barbel; Baell, Jonathan Bayldon; Cardno, Tony; Korhonen, Pasi K; Piedrafita, David Michael; Ansell, Brendan R E; Jex, Aaron R; Hofmann, Andreas; Gasser, Robin Beat.

In: International Journal for Parasitology, Vol. 45, No. 5, 2015, p. 333 - 343.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Low cost whole-organism screening of compounds for anthelmintic activity

AU - Preston, Sarah

AU - Jabbar, Abdul

AU - Nowell, Cameron J

AU - Joachim, Anja

AU - Ruttkowski, Barbel

AU - Baell, Jonathan Bayldon

AU - Cardno, Tony

AU - Korhonen, Pasi K

AU - Piedrafita, David Michael

AU - Ansell, Brendan R E

AU - Jex, Aaron R

AU - Hofmann, Andreas

AU - Gasser, Robin Beat

PY - 2015

Y1 - 2015

N2 - Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber s pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-a]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47?M. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships.

AB - Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber s pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-a]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47?M. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships.

UR - http://goo.gl/sH38RR

U2 - 10.1016/j.ijpara.2015.01.007

DO - 10.1016/j.ijpara.2015.01.007

M3 - Article

VL - 45

SP - 333

EP - 343

JO - International Journal for Parasitology

JF - International Journal for Parasitology

SN - 0020-7519

IS - 5

ER -