University of Oulu

Dans MG, Piirainen H, Nguyen W, Khurana S, Mehra S, Razook Z, et al. (2023) Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics. PLoS Biol 21(4): e3002066.

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

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Author: Dans, Madeline G.1,2,3; Piirainen, Henni4; Nguyen, William3;
Organizations: 1Burnet Institute, Melbourne, Victoria, Australia
2School of Medicine and Institute for Mental and Physical Health and Clinical Translation, Deakin University, Waurn Ponds, Victoria, Australia
3Walter and Eliza Hall Institute, Parkville, Victoria, Australia
4Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
5Ludwig Maximilian University, Faculty of Veterinary Medicine, Munich, Germany
6Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia
7Research Centre for Infectious Diseases, The University of Adelaide, Adelaide, Australia
8School of Biosciences, The University of Melbourne, Parkville, Victoria, Australia
9Department of Biomedicine, University of Bergen, Bergen, Norway
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.4 MB)
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Language: English
Published: Public Library of Science, 2023
Publish Date: 2023-09-11


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.

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Series: PLoS biology
ISSN: 1544-9173
ISSN-E: 1545-7885
ISSN-L: 1544-9173
Volume: 21
Issue: 4
Article number: e3002066
DOI: 10.1371/journal.pbio.3002066
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was supported by the National Health and Medical Research Council (2001073 to P.R.G and W.N) and (119780521 to B.S.C), the Victoria Operational Infrastructure Support Programs received by the Burnet Institute and Walter and Eliza Hall Institute, the Academy of Finland (322917 to I.K and H.P), the Sigrid Jusélius Foundation (to I.K.) and the Hospital Research Foundation (to D.W.W). This work was also funded by an Australian Government Research Training Program Scholarship (to M.G.D), a University of Melbourne Research Scholarship (to T.K.J), an Ellen Corin Fellow (to B.E.S) and an National Health and Medical Research Council Senior Research Fellowship (1136300 to TdK-W). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Academy of Finland Grant Number: 322917
Detailed Information: 322917 (Academy of Finland Funding decision)
Copyright information: © 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.