(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Maria Belen Jimenez-Diaz, Daniel Ebert, Yandira Salinas, Anupam Pradhan, Adele M Lehane, Marie-Eve Myrand-Lapierre, Kathleen G O'Loughlin, David Shackleford, Mariana Justino de Almeida, Angela Carrillo, Julie A Clark, Adelaide S M Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron N Endsley, Greg Fedewa, Wendyam Armand Guiguemde, Maria G Gomez, Gloria Holbrook & 30 others Jeremy A Horst, Charles C Kim, Jian Liu, Marcus C S Lee, Amy Matheny, Maria Santos Martinez, Gregory E Miller, Ane Rodriguez-Alejandre, Laura M Sanz, Martina Sigal, Natalie J Spillman, Philip D Stein, Zheng Wang, Fangyi Zhu, David Waterson, Spencer Knapp, Anang A Shelat, Vicky M Avery, David A Fidock, Francisco-Javier Gamo, Susan Ann Charman, Jon C Mirsalis, Hongshen Ma, Santiago B Ferrer, Kiaran Kirk, Inigo Angulo-Barturen, Dennis E Kyle, Joseph L de Risi, David M Floyd, R Kiplin Guy

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Abstract

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na+ levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na+ homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.
Original languageEnglish
Pages (from-to)e5455 - e5462
Number of pages8
JournalProceedings of the National Academy of Sciences
Volume111
Issue number50
DOIs
Publication statusPublished - 2014

Cite this

Jimenez-Diaz, M. B., Ebert, D., Salinas, Y., Pradhan, A., Lehane, A. M., Myrand-Lapierre, M-E., ... Guy, R. K. (2014). (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proceedings of the National Academy of Sciences, 111(50), e5455 - e5462. https://doi.org/10.1073/pnas.1414221111
Jimenez-Diaz, Maria Belen ; Ebert, Daniel ; Salinas, Yandira ; Pradhan, Anupam ; Lehane, Adele M ; Myrand-Lapierre, Marie-Eve ; O'Loughlin, Kathleen G ; Shackleford, David ; Justino de Almeida, Mariana ; Carrillo, Angela ; Clark, Julie A ; Dennis, Adelaide S M ; Diep, Jonathon ; Deng, Xiaoyan ; Duffy, Sandra ; Endsley, Aaron N ; Fedewa, Greg ; Guiguemde, Wendyam Armand ; Gomez, Maria G ; Holbrook, Gloria ; Horst, Jeremy A ; Kim, Charles C ; Liu, Jian ; Lee, Marcus C S ; Matheny, Amy ; Martinez, Maria Santos ; Miller, Gregory E ; Rodriguez-Alejandre, Ane ; Sanz, Laura M ; Sigal, Martina ; Spillman, Natalie J ; Stein, Philip D ; Wang, Zheng ; Zhu, Fangyi ; Waterson, David ; Knapp, Spencer ; Shelat, Anang A ; Avery, Vicky M ; Fidock, David A ; Gamo, Francisco-Javier ; Charman, Susan Ann ; Mirsalis, Jon C ; Ma, Hongshen ; Ferrer, Santiago B ; Kirk, Kiaran ; Angulo-Barturen, Inigo ; Kyle, Dennis E ; de Risi, Joseph L ; Floyd, David M ; Guy, R Kiplin. / (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. In: Proceedings of the National Academy of Sciences. 2014 ; Vol. 111, No. 50. pp. e5455 - e5462.
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title = "(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium",
abstract = "Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na+ levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na+ homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.",
author = "Jimenez-Diaz, {Maria Belen} and Daniel Ebert and Yandira Salinas and Anupam Pradhan and Lehane, {Adele M} and Marie-Eve Myrand-Lapierre and O'Loughlin, {Kathleen G} and David Shackleford and {Justino de Almeida}, Mariana and Angela Carrillo and Clark, {Julie A} and Dennis, {Adelaide S M} and Jonathon Diep and Xiaoyan Deng and Sandra Duffy and Endsley, {Aaron N} and Greg Fedewa and Guiguemde, {Wendyam Armand} and Gomez, {Maria G} and Gloria Holbrook and Horst, {Jeremy A} and Kim, {Charles C} and Jian Liu and Lee, {Marcus C S} and Amy Matheny and Martinez, {Maria Santos} and Miller, {Gregory E} and Ane Rodriguez-Alejandre and Sanz, {Laura M} and Martina Sigal and Spillman, {Natalie J} and Stein, {Philip D} and Zheng Wang and Fangyi Zhu and David Waterson and Spencer Knapp and Shelat, {Anang A} and Avery, {Vicky M} and Fidock, {David A} and Francisco-Javier Gamo and Charman, {Susan Ann} and Mirsalis, {Jon C} and Hongshen Ma and Ferrer, {Santiago B} and Kiaran Kirk and Inigo Angulo-Barturen and Kyle, {Dennis E} and {de Risi}, {Joseph L} and Floyd, {David M} and Guy, {R Kiplin}",
year = "2014",
doi = "10.1073/pnas.1414221111",
language = "English",
volume = "111",
pages = "e5455 -- e5462",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "50",

}

Jimenez-Diaz, MB, Ebert, D, Salinas, Y, Pradhan, A, Lehane, AM, Myrand-Lapierre, M-E, O'Loughlin, KG, Shackleford, D, Justino de Almeida, M, Carrillo, A, Clark, JA, Dennis, ASM, Diep, J, Deng, X, Duffy, S, Endsley, AN, Fedewa, G, Guiguemde, WA, Gomez, MG, Holbrook, G, Horst, JA, Kim, CC, Liu, J, Lee, MCS, Matheny, A, Martinez, MS, Miller, GE, Rodriguez-Alejandre, A, Sanz, LM, Sigal, M, Spillman, NJ, Stein, PD, Wang, Z, Zhu, F, Waterson, D, Knapp, S, Shelat, AA, Avery, VM, Fidock, DA, Gamo, F-J, Charman, SA, Mirsalis, JC, Ma, H, Ferrer, SB, Kirk, K, Angulo-Barturen, I, Kyle, DE, de Risi, JL, Floyd, DM & Guy, RK 2014, '(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium', Proceedings of the National Academy of Sciences, vol. 111, no. 50, pp. e5455 - e5462. https://doi.org/10.1073/pnas.1414221111

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. / Jimenez-Diaz, Maria Belen; Ebert, Daniel; Salinas, Yandira; Pradhan, Anupam; Lehane, Adele M; Myrand-Lapierre, Marie-Eve; O'Loughlin, Kathleen G; Shackleford, David; Justino de Almeida, Mariana; Carrillo, Angela; Clark, Julie A; Dennis, Adelaide S M; Diep, Jonathon; Deng, Xiaoyan; Duffy, Sandra; Endsley, Aaron N; Fedewa, Greg; Guiguemde, Wendyam Armand; Gomez, Maria G; Holbrook, Gloria; Horst, Jeremy A; Kim, Charles C; Liu, Jian; Lee, Marcus C S; Matheny, Amy; Martinez, Maria Santos; Miller, Gregory E; Rodriguez-Alejandre, Ane; Sanz, Laura M; Sigal, Martina; Spillman, Natalie J; Stein, Philip D; Wang, Zheng; Zhu, Fangyi; Waterson, David; Knapp, Spencer; Shelat, Anang A; Avery, Vicky M; Fidock, David A; Gamo, Francisco-Javier; Charman, Susan Ann; Mirsalis, Jon C; Ma, Hongshen; Ferrer, Santiago B; Kirk, Kiaran; Angulo-Barturen, Inigo; Kyle, Dennis E; de Risi, Joseph L; Floyd, David M; Guy, R Kiplin.

In: Proceedings of the National Academy of Sciences, Vol. 111, No. 50, 2014, p. e5455 - e5462.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

AU - Jimenez-Diaz, Maria Belen

AU - Ebert, Daniel

AU - Salinas, Yandira

AU - Pradhan, Anupam

AU - Lehane, Adele M

AU - Myrand-Lapierre, Marie-Eve

AU - O'Loughlin, Kathleen G

AU - Shackleford, David

AU - Justino de Almeida, Mariana

AU - Carrillo, Angela

AU - Clark, Julie A

AU - Dennis, Adelaide S M

AU - Diep, Jonathon

AU - Deng, Xiaoyan

AU - Duffy, Sandra

AU - Endsley, Aaron N

AU - Fedewa, Greg

AU - Guiguemde, Wendyam Armand

AU - Gomez, Maria G

AU - Holbrook, Gloria

AU - Horst, Jeremy A

AU - Kim, Charles C

AU - Liu, Jian

AU - Lee, Marcus C S

AU - Matheny, Amy

AU - Martinez, Maria Santos

AU - Miller, Gregory E

AU - Rodriguez-Alejandre, Ane

AU - Sanz, Laura M

AU - Sigal, Martina

AU - Spillman, Natalie J

AU - Stein, Philip D

AU - Wang, Zheng

AU - Zhu, Fangyi

AU - Waterson, David

AU - Knapp, Spencer

AU - Shelat, Anang A

AU - Avery, Vicky M

AU - Fidock, David A

AU - Gamo, Francisco-Javier

AU - Charman, Susan Ann

AU - Mirsalis, Jon C

AU - Ma, Hongshen

AU - Ferrer, Santiago B

AU - Kirk, Kiaran

AU - Angulo-Barturen, Inigo

AU - Kyle, Dennis E

AU - de Risi, Joseph L

AU - Floyd, David M

AU - Guy, R Kiplin

PY - 2014

Y1 - 2014

N2 - Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na+ levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na+ homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

AB - Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na+ levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na+ homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

UR - http://www.pnas.org/content/111/50/E5455.full.pdf+html

U2 - 10.1073/pnas.1414221111

DO - 10.1073/pnas.1414221111

M3 - Article

VL - 111

SP - e5455 - e5462

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 50

ER -