1. Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics.
- Author
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Dans MG, Piirainen H, Nguyen W, Khurana S, Mehra S, Razook Z, Geoghegan ND, Dawson AT, Das S, Parkyn Schneider M, Jonsdottir TK, Gabriela M, Gancheva MR, Tonkin CJ, Mollard V, Goodman CD, McFadden GI, Wilson DW, Rogers KL, Barry AE, Crabb BS, de Koning-Ward TF, Sleebs BE, Kursula I, and Gilson PR
- Subjects
- Humans, Plasmodium falciparum metabolism, Actins genetics, Actins metabolism, Profilins genetics, Profilins metabolism, Protozoan Proteins genetics, Protozoan Proteins metabolism, Erythrocytes parasitology, Malaria, Falciparum drug therapy, Malaria, Falciparum prevention & control, Malaria, Falciparum genetics, Antimalarials pharmacology
- Abstract
With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Dans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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