Identification and Profiling of Nematicidal Compounds in Veterinary Parasitology

Rohwer, Andreas; Lutz, Jürgen; Chassaing, Christophe; Uphoff, Manfred; Heckeroth, Anja R.; Selzer, Paul M.

doi:10.1002/9783527652969.ch9

Cited by 5 publications

(5 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The objective of the final drug discovery phase is to maintain favorable properties in lead compounds while improving any deficiencies in the lead structure. Compounds reaching this stage are considered to have met the initial goals of the lead optimization phase and are ready for final characterization before being declared as drug candidates [8,71,72].…”

Section: Approaches To Antiparasitic Developmentmentioning

confidence: 99%

Antiparasitics in Animal Health: Quo Vadis?

Selzer

Epe

2021

Trends in Parasitology

Self Cite

View full text Add to dashboard Cite

Antiparasitics acting on endo-or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions. The Animal Health IndustryAnimal health is focused on the management and control of diseases in order to ensure the health of both livestock (see Glossary) and companion animals. The global market for animal health products approaches €30 billion per year, with an annual growth rate outstripping that of human medicine. Products include biologicals (e.g., vaccines), antiparasitics/parasiticides, anti-infectives (e.g., antibiotics, antifungals), other pharmaceuticals (e.g., antihypertensives, antidiabetics), and medical feed additives (Figure 1, Key Figure). The current animal health market is understood to be driven primarily by three factors:(i) Pet owners, farmers, and veterinarians prefer more technically advanced and more convenient treatments. (ii) The growing world population increasingly demands affordable sources of protein from food animals and animal products, requiring improvements in livestock health care. (iii) The development of resistance requires new resistance-breaking preventatives and treatments.Due to the high economic impact and the immediate relevance for animal health, antiparasitics, also referred to as parasiticides, currently represent the second largest segment of the global animal health markettaking turns almost on a yearly basis with biologicals as the largest segmentaccounting for €7 billion in sales (23% of the market share) (Figures 1 and 2).In addition, animal health plays an important role in furthering the 'One Health' initiative, which is dedicated to improving the lives of all specieshuman and animalthrough the integration of human medicine, veterinary medicine, and environmental science i . The 'Antiparasitics Focus' of the Animal Health IndustryParasitic infections account for some of the most significant diseases worldwide, in both animals and humans, and are of enormous socioeconomic importance. Despite significant treatment advances in the preceding half century, they remain a major threat to livestock farming and cause large deficits for the agricultural economy. Effective parasite control is thus essential for profitability in intensive livestock production [1,2]. HighlightsAntiparasitics for the treatment of companion animals and livestock is one of the largest global market segments in the ani...

show abstract

Section: Approaches To Antiparasitic Developmentmentioning

confidence: 99%

Antiparasitics in Animal Health: Quo Vadis?

Selzer

Epe

2021

Trends in Parasitology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Most conventional in vitro-screening methods for parasitic worms have had limitations in that most of them are time-consuming to perform and/or lack repeatability/reproducibility [ 1 , 12 , 21 , 22 ]. Egg hatch- and larval development-assays are laborious, have low reproducibility and use free-living rather than parasitic stages (the target of anthelmintic treatment).…”

Section: Introductionmentioning

confidence: 99%

“…Egg hatch- and larval development-assays are laborious, have low reproducibility and use free-living rather than parasitic stages (the target of anthelmintic treatment). Phenotypic assays that measure a reduction in motility include the larval paralysis test [ 23 ] and larval migration assay [ 24 , 25 ], which are labour-intensive and rely on the visual/microscopic scoring of phenotypes or enumeration [ 21 ]. Motility measurement, based on object-tracking, has been applied to worms such as the blood fluke Schistosoma mansoni [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

et al. 2021

View full text Add to dashboard Cite

Parasitic worms cause very significant diseases in animals and humans worldwide, and their control is critical to enhance health, well-being and productivity. Due to widespread drug resistance in many parasitic worms of animals globally, there is a major, continuing demand for the discovery and development of anthelmintic drugs for use to control these worms. Here, we established a practical, cost-effective and semi-automated high throughput screening (HTS) assay, which relies on the measurement of motility of larvae of the barber’s pole worm (Haemonchus contortus) using infrared light-interference. Using this assay, we screened 80,500 small molecules and achieved a hit rate of 0.05%. We identified three small molecules that reproducibly inhibited larval motility and/or development (IC50 values of ~4 to 41 µM). Future work will critically assess the potential of selected hits as candidates for subsequent optimisation or repurposing against parasitic nematodes. This HTS assay has a major advantage over most previous assays in that it achieves a ≥ 10-times higher throughput (i.e., 10,000 compounds per week), and is thus suited to the screening of libraries of tens of thousands to hundreds of thousands of compounds for subsequent hit-to-lead optimisation or effective repurposing and development. The current assay should be adaptable to many socioeconomically important parasitic nematodes, including those that cause neglected tropical diseases (NTDs). This aspect is of relevance, given the goals of the World Health Organization (WHO) Roadmap for NTDs 2021–2030, to develop more effective drugs and drug combinations to improve patient outcomes and circumvent the ineffectiveness of some current anthelmintic drugs and possible drug resistance.

show abstract

“…A considerable limitation for the discovery of new anthelmintics or repurposing of existing chemicals as nematocides has been that many screening methods are time-consuming to carry out, lack repeatability/reproducibility or use surrogate organisms, such as Caenorhabditis elegans (Rohwer et al, 2012;Paveley and Bickle, 2013). For instance, the egg hatch test and larval development assay (LDA), which have been effective at finding new nematocides (e.g., monepantel), are usually time consuming, have low reproducibility and use free-living rather than parasitic stages of a nematode.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the egg hatch test and larval development assay (LDA), which have been effective at finding new nematocides (e.g., monepantel), are usually time consuming, have low reproducibility and use free-living rather than parasitic stages of a nematode. Phenotypic assays that measure a reduction in motility include the larval paralysis test (Martin and Le Jambre, 1979) and larval migration test (Kotze et al, 2006;Demeler et al, 2010) and usually require subjective and labour-intensive phenotypic scoring and manual counting, respectively (Rohwer et al, 2012). The measurement of motility based on object-tracking has been applied to C. elegans (www.mbfbioscience.com/wormlab) and Schistosoma mansoni (see Paveley et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Low cost whole-organism screening of compounds for anthelmintic activity

Preston

Jabbar

Nowell

et al. 2015

International Journal for Parasitology

110

206

View full text Add to dashboard Cite

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-α]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47 μM. 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.

show abstract

Identification and Profiling of Nematicidal Compounds in Veterinary Parasitology

Cited by 5 publications

References 77 publications

Antiparasitics in Animal Health: Quo Vadis?

Antiparasitics in Animal Health: Quo Vadis?

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

Low cost whole-organism screening of compounds for anthelmintic activity

Contact Info

Product

Resources

About