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

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dc.contributor.authorDans, M.G.
dc.contributor.authorPiirainen, H.
dc.contributor.authorNguyen, W.
dc.contributor.authorKhurana, S.
dc.contributor.authorMehra, S.
dc.contributor.authorRazook, Z.
dc.contributor.authorGeoghegan, N.D.
dc.contributor.authorDawson, A.T.
dc.contributor.authorDas, S.
dc.contributor.authorParkyn Schneider, M.
dc.contributor.authorJonsdottir, T.K.
dc.contributor.authorGabriela, M.
dc.contributor.authorGancheva, M.R.
dc.contributor.authorTonkin, C.J.
dc.contributor.authorMollard, V.
dc.contributor.authorGoodman, C.D.
dc.contributor.authorMcFadden, G.I.
dc.contributor.authorWilson, D.W.
dc.contributor.authorRogers, K.L.
dc.contributor.authorBarry, A.E.
dc.contributor.authoret al.
dc.contributor.editorKim, K.
dc.date.issued2023
dc.descriptionPublished: April 13, 2023
dc.description.abstractWith 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.
dc.description.statementofresponsibilityMadeline G. Dans, Henni Piirainen, William Nguyen, Sachin Khurana, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Aurelie T. Dawson, Sujaan Das, Molly Parkyn Schneider, Thorey K. Jonsdottir, Mikha Gabriela, Maria R. Gancheva, Christopher J. Tonkin, Vanessa Mollard, Christopher Dean Goodman, Geoffrey I. McFadden, Danny W. Wilson, Kelly L. Rogers, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning-Ward, Brad E. Sleebs, Inari Kursula, Paul R. Gilson
dc.identifier.citationPLoS Biology, 2023; 21(4):e3002066-1-e3002066-34
dc.identifier.doi10.1371/journal.pbio.3002066
dc.identifier.issn1544-9173
dc.identifier.issn1545-7885
dc.identifier.orcidGancheva, M.R. [0000-0001-7428-6791]
dc.identifier.orcidWilson, D.W. [0000-0002-5073-1405]
dc.identifier.urihttps://hdl.handle.net/2440/138335
dc.language.isoen
dc.publisherPublic Library of Science (PLoS)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2001073
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1197805
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1136300
dc.rights© 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.
dc.source.urihttps://doi.org/10.1371/journal.pbio.3002066
dc.subjectErythrocytes
dc.subjectHumans
dc.subjectPlasmodium falciparum
dc.subjectMalaria, Falciparum
dc.subjectActins
dc.subjectProtozoan Proteins
dc.subjectAntimalarials
dc.subjectProfilins
dc.subject.meshErythrocytes
dc.subject.meshHumans
dc.subject.meshPlasmodium falciparum
dc.subject.meshMalaria, Falciparum
dc.subject.meshActins
dc.subject.meshProtozoan Proteins
dc.subject.meshAntimalarials
dc.subject.meshProfilins
dc.titleSulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics
dc.typeJournal article
pubs.publication-statusPublished online

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