Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13

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Abstract

Haemonchus contortus, one of the most economically important parasites of small ruminants, has become resistant to the anthelmintic ivermectin. Deciphering the role of P-glycoproteins in ivermectin resistance is desirable for understanding and overcoming this resistance. In the model nematode, Caenorhabditis elegans, P-glycoprotein-13 is expressed in the amphids, important neuronal structures for ivermectin activity. We have focused on its ortholog in the parasite, Hco-Pgp-13. A 3D model of Hco-Pgp-13, presenting an open inward-facing conformation, has been constructed by homology with the Cel-Pgp-1 crystal structure. In silico docking calculations predicted high affinity binding of ivermectin and actinomycin D to the inner chamber of the protein. Following in vitro expression, we showed that ivermectin and actinomycin D modulated Hco-Pgp-13 ATPase activity with high affinity. Finally, we found in vivo Hco-Pgp-13 localization in epithelial, pharyngeal and neuronal tissues. Taken together, these data suggest a role for Hco-Pgp-13 in ivermectin transport, which could contribute to anthelmintic resistance.

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David, M., Lebrun, C., Duguet, T., Talmont, F., Beech, R., Orlowski, S., … Lespine, A. (2018). Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13. International Journal for Parasitology: Drugs and Drug Resistance, 8(1), 145–157. https://doi.org/10.1016/j.ijpddr.2018.02.001

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