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 S Nagle; Marcin Stasiak; Susan Ann Charman; Inigo Angulo-Barturen; Santiago B Ferrer; Maria Belen Jimenez-Diaz; Maria Santos Martinez; Francisco Javier Gamo-Benito; Vicky M Avery; Andrea Ruecker; Michael J 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 S Nagle, Marcin Stasiak, Susan Ann Charman, Inigo Angulo-Barturen, Santiago B Ferrer, Maria Belen Jimenez-DiazMaria Santos Martinez, Francisco Javier Gamo-Benito, Vicky M Avery, Andrea Ruecker, Michael J Delves, Kiaran Kirk, Matthew Berriman, Sandhya Kortagere, Jeremy Burrows, Erkang Fan, Lawrence W Bergman

Centre for Drug Candidate Optimisation

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

92 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
Pages (from-to)	1 - 10
Number of pages	10
Journal	Nature Communications
Volume	5
Issue number	5521
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. S., Stasiak, M., Charman, S. A., Angulo-Barturen, I., Ferrer, S. B., ... Bergman, L. W. (2014). Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications, 5(5521), 1 - 10. https://doi.org/10.1038/ncomms6521

@article{e42b43ad115b4dcc89ced83dfbdada1d,

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 Nagle, {Advait S} and Marcin Stasiak and Charman, {Susan Ann} and Inigo Angulo-Barturen and Ferrer, {Santiago B} and Jimenez-Diaz, {Maria Belen} and Martinez, {Maria Santos} and Gamo-Benito, {Francisco Javier} and Avery, {Vicky M} and Andrea Ruecker and Delves, {Michael J} 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",

pages = "1 -- 10",

journal = "Nature Communications",

issn = "2041-1723",

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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, AS, Stasiak, M, Charman, SA, Angulo-Barturen, I, Ferrer, SB, Jimenez-Diaz, MB, Martinez, MS, Gamo-Benito, FJ, Avery, VM, Ruecker, A, Delves, MJ, 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, no. 5521, pp. 1 - 10. 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 S

AU - Stasiak, Marcin

AU - Charman, Susan Ann

AU - Angulo-Barturen, Inigo

AU - Ferrer, Santiago B

AU - Jimenez-Diaz, Maria Belen

AU - Martinez, Maria Santos

AU - Gamo-Benito, Francisco Javier

AU - Avery, Vicky M

AU - Ruecker, Andrea

AU - Delves, Michael J

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 - http://www.nature.com/ncomms/2014/141125/ncomms6521/pdf/ncomms6521.pdf

U2 - 10.1038/ncomms6521

DO - 10.1038/ncomms6521

M3 - Article

VL - 5

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 5521

ER -

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

Abstract

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