A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4

Gilson, Paul R., Kumarasingha, Rasika, Thompson, Jennifer, Zhang, Xinxin, Penington, Jocelyn S., Kalhor, Robabeh, Bullen, Hayley E., Lehane, Adele M., Dans, Madeline G., De Koning-Ward, Tania, Holien, Jessica K., Soares da Costa, Tatiana P., Hulett, Mark D., Buskes, Melissa J., Crabb, Brendan S., Kirk, Kiaran, Papenfuss, Anthony T., Cowman, Alan F. and Abbott, Belinda M. 2019, A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4, Scientific reports, vol. 9, no. 1, doi: 10.1038/s41598-019-46500-5.

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Title A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4
Author(s) Gilson, Paul R.
Kumarasingha, Rasika
Thompson, Jennifer
Zhang, Xinxin
Penington, Jocelyn S.
Kalhor, Robabeh
Bullen, Hayley E.
Lehane, Adele M.
Dans, Madeline G.
De Koning-Ward, TaniaORCID iD for De Koning-Ward, Tania orcid.org/0000-0001-5810-8063
Holien, Jessica K.
Soares da Costa, Tatiana P.
Hulett, Mark D.
Buskes, Melissa J.
Crabb, Brendan S.
Kirk, Kiaran
Papenfuss, Anthony T.
Cowman, Alan F.
Abbott, Belinda M.
Journal name Scientific reports
Volume number 9
Issue number 1
Article ID 10292
Total pages 15
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2019-07-16
ISSN 2045-2322
Keyword(s) Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
DEPENDENT PROTEIN-KINASE
CATION ATPASE PFATP4
MALARIA PARASITE
SPIROINDOLONE KAE609
RESISTANCE
IDENTIFICATION
TRANSPORTER
CANDIDATE
INVASION
MUTATION
Summary © 2019, The Author(s). We developed a novel series of antimalarial compounds based on a 4-cyano-3-methylisoquinoline. Our lead compound MB14 achieved modest inhibition of the growth in vitro of the human malaria parasite, Plasmodium falciparum. To identify its biological target we selected for parasites resistant to MB14. Genome sequencing revealed that all resistant parasites bore a single point S374R mutation in the sodium (Na+) efflux transporter PfATP4. There are many compounds known to inhibit PfATP4 and some are under preclinical development. MB14 was shown to inhibit Na+ dependent ATPase activity in parasite membranes, consistent with the compound targeting PfATP4 directly. PfATP4 inhibitors cause swelling and lysis of infected erythrocytes, attributed to the accumulation of Na+ inside the intracellular parasites and the resultant parasite swelling. We show here that inhibitor-induced lysis of infected erythrocytes is dependent upon the parasite protein RhopH2, a component of the new permeability pathways that are induced by the parasite in the erythrocyte membrane. These pathways mediate the influx of Na+ into the infected erythrocyte and their suppression via RhopH2 knockdown limits the accumulation of Na+ within the parasite hence protecting the infected erythrocyte from lysis. This study reveals a role for the parasite-induced new permeability pathways in the mechanism of action of PfATP4 inhibitors.
Language eng
DOI 10.1038/s41598-019-46500-5
Indigenous content off
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2019, The Authors
Persistent URL http://hdl.handle.net/10536/DRO/DU:30128441

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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