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Vet Parasitol. 2019 Jan;265:15-18. doi: 10.1016/j.vetpar.2018.11.014. Epub 2018 Dec 7.

Screening of a drug repurposing library with a nematode motility assay identifies promising anthelmintic hits against Cooperia oncophora and other ruminant parasites.

Author information

1
Center of antibody drug, Institute of biomedicine and biotechnology, Shenzhen institutes of advanced technology, Chinese Academy of Science, Shenzhen, 518055, China; Department of Biology, Animal Physiology and Neurobiology Section, KU Leuven, Naamsestraat 59, box 2465, 3000 Leuven, Belgium; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, box 921, 3000 Leuven, Belgium. Electronic address: liumaoxuan2008@gmail.com.
2
Department of Biology, Animal Physiology and Neurobiology Section, KU Leuven, Naamsestraat 59, box 2465, 3000 Leuven, Belgium.
3
Cistim Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, 3001 Leuven, Belgium.
4
Laboratory of Parasitology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke B-9820, Belgium.

Abstract

Parasitic nematodes continue to cause significant economic losses in livestock globally. Given the limited number of anthelmintic drugs on the market and the currently increasing drug resistance, there is an urgent need for novel anthelmintics. Most motility assays of anthelmintic activity for parasitic nematodes are laborious and low throughput, and therefore not suitable for screening large compound libraries. Cooperia oncophora accounts for a large proportion of reports on the drug-resistance development of parasites globally. Therefore, using a WMicroTracker instrument, we established a practical, automated and low-cost whole-organism motility assay against exsheathed L3 stages (xL3s) of the ruminant parasite Cooperia oncophora, and screened a repurposing library comprising 2745 molecules. Fourteen known anthelmintics contained in this library were picked up in this blind screen, as well as four novel hits: thonzonium bromide, NH125, physostigmine sulfate, and EVP4593. The four hits were also active against xL3s of Ostertagia ostertagi, Haemonchus contortus and Teladorsagia circumcincta using the same assay. Cytotoxicity testing showed that thonzonium bromide and NH125 (1-Benzyl-3-cetyl-2-methylimidazolium iodide) have significant cytotoxicity. EVP4593 (N(4)-(2-(4-phenoxyphenyl)ethyl)-4,6-quinazolinediamine) demonstrated a potent and broad anthelmintic activity, and a high selectivity index. Moreover, given its novel and unexplored chemical scaffold for anthelmintic activity, EVP4593 is an interesting anthelmintic hit for further optimization.

KEYWORDS:

Anthelmintic; Cooperia oncophora; EPV4593; Motility assay; Repurposing library

PMID:
30638515
DOI:
10.1016/j.vetpar.2018.11.014
[Indexed for MEDLINE]

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