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

  • Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5455-62. doi: 10.1073/pnas.1414221111.
María Belén Jiménez-Díaz  1 ,  Daniel Ebert  2 ,  Yandira Salinas  3 ,  Anupam Pradhan  4 ,  Adele M Lehane  5 ,  Marie-Eve Myrand-Lapierre  6 ,  Kathleen G O'Loughlin  7 ,  David M Shackleford  8 ,  Mariana Justino de Almeida  9 ,  Angela K Carrillo  3 ,  Julie A Clark  3 ,  Adelaide S M Dennis  5 ,  Jonathon Diep  2 ,  Xiaoyan Deng  6 ,  Sandra Duffy  10 ,  Aaron N Endsley  7 ,  Greg Fedewa  2 ,  W Armand Guiguemde  3 ,  María G Gómez  1 ,  Gloria Holbrook  3 ,  Jeremy Horst  2 ,  Charles C Kim  11 ,  Jian Liu  12 ,  Marcus C S Lee  9 ,  Amy Matheny  3 ,  María Santos Martínez  1 ,  Gregory Miller  3 ,  Ane Rodríguez-Alejandre  1 ,  Laura Sanz  1 ,  Martina Sigal  3 ,  Natalie J Spillman  5 ,  Philip D Stein  12 ,  Zheng Wang  12 ,  Fangyi Zhu  3 ,  David Waterson  13 ,  Spencer Knapp  12 ,  Anang Shelat  3 ,  Vicky M Avery  10 ,  David A Fidock  9 ,  Francisco-Javier Gamo  1 ,  Susan A Charman  8 ,  Jon C Mirsalis  7 ,  Hongshen Ma  6 ,  Santiago Ferrer  1 ,  Kiaran Kirk  5 ,  Iñigo Angulo-Barturen  1 ,  Dennis E Kyle  4 ,  Joseph L DeRisi  2 ,  David M Floyd  12 ,  R Kiplin Guy  14
Affiliations
  • 1. Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
  • 2. Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2330;
  • 3. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
  • 4. Department of Global Health, College of Public Health, University of South Florida, Tampa, FL 33612;
  • 5. Research School of Biology, Australian National University, Canberra, ACT, Australia 2601;
  • 6. Departments of Mechanical Engineering and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
  • 7. Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA 94025;
  • 8. Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia 3052;
  • 9. Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
  • 10. Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, QLD, Australia 4111;
  • 11. Division of Experimental Medicine, University of California, San Francisco, CA 94110;
  • 12. Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
  • 13. Medicines for Malaria Venture, International Center Cointrin, 1215 Geneva, Switzerland.
  • 14. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105; [email protected].
PMID: 25453091 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.

Keywords
PfATP4; drug discovery; malaria.
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