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

01 Dec 2014

María Belén Jiménez-Díaz, Daniel Ebert, Yandira Salinas, Anupam Pradhan, Adele M. Lehane, Marie-Eve Myrand-Lapierre, Kathleen G. O’ Loughlin, David M. Shackleford, Mariana Justino de Almeida, Angela K. Carrillo, Julie A. Clark, Adelaide S. M. Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron N. Endsley, Greg Fedewa, W. Armand Guiguemde, María G. Gómez, Gloria Holbrook, Jeremy Horst, Charles C. Kim, Jian Liu, Marcus C. S. Lee, Amy Matheny, María Santos Martínez, Gregory Miller, Ane Rodríguez-Alejandre, Laura Sanz, Martina Sigal, Natalie J. Spillman, Philip D. Stein, Zheng Wang, Fangyi Zhu, David Waterson, Spencer Knapp, Anang Shelat, Vicky M. Avery, David A. Fidock, Francisco-Javier Gamo, Susan A. Charman, Jon C. Mirsalis, Hongshen Ma, Santiago Ferrer, Kiaran Kirk, Iñigo Angulo-Barturen, Dennis E. Kyle, Joseph L. DeRisi, David M. Floyd, and R. Kiplin Guy

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

DOI: 10.1073/pnas.1414221111

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.

Read the full article on the PNAS website.