Filarial nematode phenotypic screening cascade to identify compounds with anti-parasitic activity for drug discovery optimization

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite....

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Published in:International journal for parasitology -- drugs and drug resistance 2022-08, Vol.19, p.89-97
Main Authors: Hawryluk, Natalie, Zhiru, Li, Carlow, Clotilde, Gokool, Suzanne, Townson, Simon, Kreiss, Tamara, Chojnowski, Agnieszka, Prorok, Monika, Siekierka, John, Ehrens, Alexandra, Koschel, Marianne, Lhermitte-Vallarino, Nathaly, Martin, Coralie, Hoerauf, Achim, Hernandez, Geraldine, Canan, Stacie, Khetani, Vikram, Zeldis, Jerome, Specht, Sabine, Hübner, Marc P., Scandale, Ivan
Format: Article
Language:English
Subjects:
Chemical Sciences
Life Sciences
Regular article
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Summary:Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite. Drug discovery efforts are challenged by the lack of preclinical animal models using the human-pathogenic filariae, requiring the use of surrogate parasites for Onchocerca volvulus for both ex vivo and in vivo evaluation. Herein, we describe a platform utilizing phenotypic ex vivo assays consisting of the free-living nematode Caenorhabditis elegans , microfilariae and adult filariae of the bovine filariae Onchocerca lienalis and Onchocerca gutturosa , respectively, as well as microfilariae and adult filariae of the feline filariae Brugia pahangi , the rodent filariae Litomosoides sigmodontis and the human-pathogenic filariae Brugia malayi to assess activity across various surrogate parasites. Utilization of those surrogate nematodes for phenotypic ex vivo assays in order to assess activity across various parasites led to the successful establishment of a screening cascade and identification of multiple compounds with potential macrofilaricidal activity and desirable physicochemical, MW = 200–400 and low lipophilicity, logP
ISSN:2211-3207
2211-3207
DOI:10.1016/j.ijpddr.2022.06.002