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

PR Gilson; R Kumarasingha; J Thompson; X Zhang; JS Penington; R Kalhor; HE Bullen; AM Lehane; MG Dans; TF de Koning-Ward; JK Holien; TP Soares da Costa; MD Hulett; MJ Buskes; BS Crabb; K Kirk; AT Papenfuss; AF Cowman; BM Abbott

Journal article

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

PR Gilson, R Kumarasingha, J Thompson, X Zhang, JS Penington, R Kalhor, HE Bullen, AM Lehane, MG Dans, TF de Koning-Ward, JK Holien, TP Soares da Costa, MD Hulett, MJ Buskes, BS Crabb, K Kirk, AT Papenfuss, AF Cowman, BM Abbott

Scientific Reports | NATURE PORTFOLIO | Published : 2019

DOI: 10.1038/s41598-019-46500-5

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Abstract

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 ..

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University of Melbourne Researchers

Madeline Dans Author

Jessica Holien Author

Brendan Crabb Author

Tony Papenfuss Author

Related Projects (1)

INTERACTION OF MALARIA PARASITES WITH THE HOST DISEASE PATHOGENESIS AND CONTROL

Grants

Awarded by National Health and Medical Research Council

Funding Acknowledgements

We thank the Melbourne and Canberra branches of the Australian Red Cross Blood Bank for the provision of human blood. We are grateful to Stephen Wilcox for the Next Generation sequencing, conducted at the Ian Potter Centre for Genomics within the Walter and Eliza Hall Institute for Medical Research, Victoria Australia. M.G.D. is the recipient of an Australian Government Research Training Program (RTP) Scholarship. A.M.L. is supported by an Australian Research Council Discovery Early Career Researcher Award (DE160101035). T.P.S.C. is supported by NHMRC fellowship funding 1091976. The authors gratefully acknowledge funding from the Victorian Operational Infrastructure Support Program received by the Burnet Institute and for grants from the National Health and Medical Research Council of Australia (1068287, 1021560, 637406 and 1042272) and the Australian Research Council (LP150101226).