Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics

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; Gilson, PR

Author(s): 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; Gilson, PR;
Details: Publication Year 2023-04-13,Volume 21,Issue #4,Page e3002066
Journal Title: PLoS Biology
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.
Publisher: PLOS
Research Division(s): Chemical Biology
PubMed ID: 37053271
Publisher's Version: https://doi.org/10.1371/journal.pbio.3002066
Open Access at Publisher's Site: https://doi.org/10.1371/journal.pbio.3002066
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-04-17 03:38:13

Last Modified: 2023-04-18 02:19:55