(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium
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, R Kiplin Guy, 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, R Kiplin Guy
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.
Keywords: PfATP4; drug discovery; malaria.
Conflict of interest statement
Conflict of interest statement: M.B.J.-D., M.G.G., M.S.M., A.R.-A., L.S., F-J.G., S.F., and I.A.-B. are employees of GlaxoSmithKline and are engaged in commercial development of antimalarial drugs, although not this compound.
Figures
References
- World Health Organization . World Malaria Report. WHO; Geneva: 2012.
- Anthony MP, Burrows JN, Duparc S, Moehrle JJ, Wells TN. The global pipeline of new medicines for the control and elimination of malaria. Malar J. 2012;11:316.
- Spangenberg T, et al. The open access malaria box: A drug discovery catalyst for neglected diseases. PLoS ONE. 2013;8(6):e62906.
- Burrows JN, van Huijsduijnen RH, Möhrle JJ, Oeuvray C, Wells TN. Designing the next generation of medicines for malaria control and eradication. Malar J. 2013;12:187.
- Chatterjee AK, Yeung BK. Back to the future: Lessons learned in modern target-based and whole-cell lead optimization of antimalarials. Curr Top Med Chem. 2012;12(5):473–483.
- Neafsey DE. Genome sequencing sheds light on emerging drug resistance in malaria parasites. Nat Genet. 2013;45(6):589–590.
- Guiguemde WA, et al. Chemical genetics of Plasmodium falciparum. Nature. 2010;465(7296):311–315.
- Rottmann M, et al. Spiroindolones, a potent compound class for the treatment of malaria. Science. 2010;329(5996):1175–1180.
- Jiménez-Díaz MB, et al. Improved murine model of malaria using Plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2Rgammanull mice engrafted with human erythrocytes. Antimicrob Agents Chemother. 2009;53(10):4533–4536.
- Park DJ, et al. Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite. Proc Natl Acad Sci USA. 2012;109(32):13052–13057.
- Xie C, Tammi MT. CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics. 2009;10:80.
- Spillman NJ, et al. Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe. 2013;13(2):227–237.
- Spillman NJ, Allen RJ, Kirk K. Na+ extrusion imposes an acid load on the intraerythrocytic malaria parasite. Mol Biochem Parasitol. 2013;189(1-2):1–4.
- Rathod PK, Leffers NP, Young RD. Molecular targets of 5-fluoroorotate in the human malaria parasite, Plasmodium falciparum. Antimicrob Agents Chemother. 1992;36(4):704–711.
- Lutz HU, Bogdanova A. Mechanisms tagging senescent red blood cells for clearance in healthy humans. Front Physiol. 2013;4:387.
- Lee SJ, Park SY, Jung MY, Bae SM, Kim IS. Mechanism for phosphatidylserine-dependent erythrophagocytosis in mouse liver. Blood. 2011;117(19):5215–5223.
- Kwan JM, Guo Q, Kyluik-Price DL, Ma H, Scott MD. Microfluidic analysis of cellular deformability of normal and oxidatively damaged red blood cells. Am J Hematol. 2013;88(8):682–689.
- Mohandas N, Groner W. Cell membrane and volume changes during red cell development and aging. Ann N Y Acad Sci. 1989;554:217–224.
- de Back DZ, Kostova EB, van Kraaij M, van den Berg TK, van Bruggen R. Of macrophages and red blood cells: A complex love story. Front Physiol. 2014;5:9.
- Schwartz RS, et al. Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes. J Clin Invest. 1985;75(6):1965–1972.
- Schroit AJ, Madsen JW, Tanaka Y. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem. 1985;260(8):5131–5138.
- Klausner MA, et al. Contrasting splenic mechanisms in the blood clearance of red blood cells and colloidal particles. Blood. 1975;46(6):965–976.
- Föller M, et al. Suicide for survival—death of infected erythrocytes as a host mechanism to survive malaria. Cell Physiol Biochem. 2009;24(3-4):133–140.
- Piagnerelli M, et al. Assessment of erythrocyte shape by flow cytometry techniques. J Clin Pathol. 2007;60(5):549–554.
- Ahlgrim C, Pottgiesser T, Sander T, Schumacher YO, Baumstark MW. Flow cytometric assessment of erythrocyte shape through analysis of FSC histograms: Use of kurtosis and implications for longitudinal evaluation. PLoS ONE. 2013;8(3):e59862.
- Guo Q, Reiling SJ, Rohrbach P, Ma H. Microfluidic biomechanical assay for red blood cells parasitized by Plasmodium falciparum. Lab Chip. 2012;12(6):1143–1150.
- Evans E, Leung A. Adhesivity and rigidity of erythrocyte membrane in relation to wheat germ agglutinin binding. J Cell Biol. 1984;98(4):1201–1208.
- Williams RJ, Shaw SK. The relationship between cell injury and osmotic volume reduction: II. Red cell lysis correlates with cell volume rather than intracellular salt concentration. Cryobiology. 1980;17(6):530–539.
- Lee P, Ye Z, Van Dyke K, Kirk RG. X-ray microanalysis of Plasmodium falciparum and infected red blood cells: Effects of qinghaosu and chloroquine on potassium, sodium, and phosphorus composition. Am J Trop Med Hyg. 1988;39(2):157–165.
- White NJ, et al. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med. 2014;371(5):403–410.
Source: PubMed