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

authors

• David Marion
• Lebrun Chantal
• Duguet Thomas
• Talmont Franck
• Beech Robin
• Orlowski Stéphane
• André François
• Prichard Roger K.
• Lespine Anne

keywords

• ABC transporters
• Haemonchus contortus
• Homology modeling
• Ivermectin
• Nematode
• P-glycoprotein

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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