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Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound

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Kieffer, C. | Primas, N. | Hutter, S. | Merckx, A. | Reininger, L. | Bach, S. | Ruchaud, S. | Gaillard, F. | Laget, M. | Amrane, D. | Hervé, L. | Castera-Ducros, C. | Renault, J. | Dumètre, A. | Rault, S. | Doerig, C. | Rathelot, P. | Vanelle, P. | Azas, N. | Verhaeghe, P.

Edité par CCSD ; Elsevier -

International audience. We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate. Several anchoring positions of the linker (6,7 and 3′) and PEG-type linkers were assessed, to obtain a linked-hit molecule displaying in vitro antiplasmodial activity similar to that of unmodified Hit A. This allowed us to identify the PfPYK-1 kinase and the PfRab6 GTP-ase as potential targets of Hit A.

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