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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 50; pp. E5455 - E5462
• Main Authors: Jiménez-Díaz, María Belén, Ebert, Daniel, Salinas, Yandira, Pradhan, Anupam, Lehane, Adele M, Myrand-Lapierre, Marie-Eve, O'Loughlin, Kathleen G, Shackleford, David M, Justino de Almeida, Mariana, Carrillo, Angela K, Clark, Julie A, Dennis, Adelaide S M, Diep, Jonathon, Deng, Xiaoyan, Duffy, Sandra, Endsley, Aaron N, Fedewa, Greg, Guiguemde, W Armand, Gómez, María G, Holbrook, Gloria, Horst, Jeremy, Kim, Charles C, Liu, Jian, Lee, Marcus C S, Matheny, Amy, Martínez, María Santos, Miller, Gregory, Rodríguez-Alejandre, Ane, Sanz, Laura, Sigal, Martina, Spillman, Natalie J, Stein, Philip D, Wang, Zheng, Zhu, Fangyi, Waterson, David, Knapp, Spencer, Shelat, Anang, Avery, Vicky M, Fidock, David A, Gamo, Francisco-Javier, Charman, Susan A, Mirsalis, Jon C, Ma, Hongshen, Ferrer, Santiago, Kirk, Kiaran, Angulo-Barturen, Iñigo, Kyle, Dennis E, DeRisi, Joseph L, Floyd, David M, Guy, R Kiplin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.12.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Adenosine triphosphatase; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Biological Sciences; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Cellular Senescence - drug effects; Drug Discovery; Drug Resistance - genetics; Erythrocytes; Erythrocytes - drug effects; Flow Cytometry; Heterocyclic Compounds, 4 or More Rings - pharmacokinetics; Heterocyclic Compounds, 4 or More Rings - pharmacology; High-Throughput Screening Assays; Homeostasis; Isoquinolines - pharmacokinetics; Isoquinolines - pharmacology; Malaria; Malaria - drug therapy; Models, Molecular; Molecular Structure; Mutation; Parasitic protozoa; Plasmodium - drug effects; Plasmodium falciparum; PNAS Plus; drug discovery; malaria; PfATP4
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1414221111

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. Significance Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.