Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

Akhil B. Vaidya; Joanne M. Morrisey; Zhongsheng Zhang; Sudipta Das; Thomas M. Daly; Thomas D. Otto; Natalie J. Spillman; Matthew Wyvratt; Peter Siegl; Jutta Marfurt; Grennady Wirjanata; Boni F. Sebayang; Ric N. Price; Arnab Chatterjee; Advait Nagle; Marcin Stasiak; Susan A. Charman; Iñigo Angulo-Barturen; Santiago Ferrer; María Belén Jiménez-Díaz; María Santos Martínez; Francisco Javier Gamo; Vicky M. Avery; Andrea Ruecker; Michael Delves; Kiaran Kirk; Matthew Berriman; Sandhya Kortagere; Jeremy Burrows; Erkang Fan; Lawrence W. Bergman

doi:10.1038/ncomms6521

Pyrazoleamide compounds are potent antimalarials that target Na⁺ homeostasis in intraerythrocytic Plasmodium falciparum

Akhil B. Vaidya^*
, Joanne M. Morrisey
, Zhongsheng Zhang
, Sudipta Das
, Thomas M. Daly
, Thomas D. Otto
, Natalie J. Spillman
, Matthew Wyvratt
, Peter Siegl
, Jutta Marfurt
, Grennady Wirjanata
, Boni F. Sebayang
, Ric N. Price
, Arnab Chatterjee
, Advait Nagle
, Marcin Stasiak
, Susan A. Charman
, Iñigo Angulo-Barturen
, Santiago Ferrer
, María Belén Jiménez-Díaz

María Santos Martínez, Francisco Javier Gamo, Vicky M. Avery, Andrea Ruecker, Michael Delves, Kiaran Kirk, Matthew Berriman, Sandhya Kortagere, Jeremy Burrows, Erkang Fan, Lawrence W. Bergman

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

115 Citations (Scopus)

Abstract

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na⁺ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na⁺ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na⁺ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

Original language	English
Article number	5521
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6521
Publication status	Published - 2014

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Vaidya, A. B., Morrisey, J. M., Zhang, Z., Das, S., Daly, T. M., Otto, T. D., Spillman, N. J., Wyvratt, M., Siegl, P., Marfurt, J., Wirjanata, G., Sebayang, B. F., Price, R. N., Chatterjee, A., Nagle, A., Stasiak, M., Charman, S. A., Angulo-Barturen, I., Ferrer, S., ... Bergman, L. W. (2014). Pyrazoleamide compounds are potent antimalarials that target Na⁺ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications, 5, Article 5521. https://doi.org/10.1038/ncomms6521

@article{b833a37394944b98b07f07716851a500,

title = "Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum",

abstract = "The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.",

author = "Vaidya, \{Akhil B.\} and Morrisey, \{Joanne M.\} and Zhongsheng Zhang and Sudipta Das and Daly, \{Thomas M.\} and Otto, \{Thomas D.\} and Spillman, \{Natalie J.\} and Matthew Wyvratt and Peter Siegl and Jutta Marfurt and Grennady Wirjanata and Sebayang, \{Boni F.\} and Price, \{Ric N.\} and Arnab Chatterjee and Advait Nagle and Marcin Stasiak and Charman, \{Susan A.\} and I{\~n}igo Angulo-Barturen and Santiago Ferrer and \{Bel{\'e}n Jim{\'e}nez-D{\'i}az\}, Mar{\'i}a and Mart{\'i}nez, \{Mar{\'i}a Santos\} and Gamo, \{Francisco Javier\} and Avery, \{Vicky M.\} and Andrea Ruecker and Michael Delves and Kiaran Kirk and Matthew Berriman and Sandhya Kortagere and Jeremy Burrows and Erkang Fan and Bergman, \{Lawrence W.\}",

year = "2014",

doi = "10.1038/ncomms6521",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Vaidya, AB, Morrisey, JM, Zhang, Z, Das, S, Daly, TM, Otto, TD, Spillman, NJ, Wyvratt, M, Siegl, P, Marfurt, J, Wirjanata, G, Sebayang, BF, Price, RN, Chatterjee, A, Nagle, A, Stasiak, M, Charman, SA, Angulo-Barturen, I, Ferrer, S, Belén Jiménez-Díaz, M, Martínez, MS, Gamo, FJ, Avery, VM, Ruecker, A, Delves, M, Kirk, K, Berriman, M, Kortagere, S, Burrows, J, Fan, E & Bergman, LW 2014, 'Pyrazoleamide compounds are potent antimalarials that target Na⁺ homeostasis in intraerythrocytic Plasmodium falciparum', Nature Communications, vol. 5, 5521. https://doi.org/10.1038/ncomms6521

TY - JOUR

T1 - Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

AU - Vaidya, Akhil B.

AU - Morrisey, Joanne M.

AU - Zhang, Zhongsheng

AU - Das, Sudipta

AU - Daly, Thomas M.

AU - Otto, Thomas D.

AU - Spillman, Natalie J.

AU - Wyvratt, Matthew

AU - Siegl, Peter

AU - Marfurt, Jutta

AU - Wirjanata, Grennady

AU - Sebayang, Boni F.

AU - Price, Ric N.

AU - Chatterjee, Arnab

AU - Nagle, Advait

AU - Stasiak, Marcin

AU - Charman, Susan A.

AU - Angulo-Barturen, Iñigo

AU - Ferrer, Santiago

AU - Belén Jiménez-Díaz, María

AU - Martínez, María Santos

AU - Gamo, Francisco Javier

AU - Avery, Vicky M.

AU - Ruecker, Andrea

AU - Delves, Michael

AU - Kirk, Kiaran

AU - Berriman, Matthew

AU - Kortagere, Sandhya

AU - Burrows, Jeremy

AU - Fan, Erkang

AU - Bergman, Lawrence W.

PY - 2014

Y1 - 2014

N2 - The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

AB - The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

UR - https://www.scopus.com/pages/publications/84923311088

U2 - 10.1038/ncomms6521

DO - 10.1038/ncomms6521

M3 - Article

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 5521

ER -

Pyrazoleamide compounds are potent antimalarials that target Na⁺ homeostasis in intraerythrocytic Plasmodium falciparum

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