Journal article
Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics
MG Dans, H Piirainen, W Nguyen, S Khurana, S Mehra, Z Razook, ND Geoghegan, AT Dawson, S Das, MP Schneider, TK Jonsdottir, M Gabriela, MR Gancheva, CJ Tonkin, V Mollard, CD Goodman, GI McFadden, DW Wilson, KL Rogers, AE Barry Show all
Plos Biology | Published : 2023
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 MMV02..
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Awarded by University of Melbourne
Funding Acknowledgements
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 Juselius 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.