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.
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2330;
authors.forename: Daniel
authors.initials: D
authors.lastname: Ebert
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Yandira
authors.initials: Y
authors.lastname: Salinas
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, FL 33612;
authors.forename: Anupam
authors.initials: A
authors.lastname: Pradhan
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT, Australia 2601;
authors.forename: Adele M
authors.initials: AM
authors.lastname: Lehane
authors.affiliation: Departments of Mechanical Engineering and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Myrand-Lapierre
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA 94025;
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: O'Loughlin
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia 3052;
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: Mariana
authors.initials: M
authors.lastname: Justino de Almeida
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Angela K
authors.initials: AK
authors.lastname: Carrillo
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Julie A
authors.initials: JA
authors.lastname: Clark
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT, Australia 2601;
authors.forename: Adelaide S M
authors.initials: AS
authors.lastname: Dennis
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2330;
authors.forename: Jonathon
authors.initials: J
authors.lastname: Diep
authors.affiliation: Departments of Mechanical Engineering and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, QLD, Australia 4111;
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA 94025;
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Endsley
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2330;
authors.forename: Greg
authors.initials: G
authors.lastname: Fedewa
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: María G
authors.initials: MG
authors.lastname: Gómez
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Gloria
authors.initials: G
authors.lastname: Holbrook
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2330;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Horst
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Charles C
authors.initials: CC
authors.lastname: Kim
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Amy
authors.initials: A
authors.lastname: Matheny
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Gregory
authors.initials: G
authors.lastname: Miller
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: Ane
authors.initials: A
authors.lastname: Rodríguez-Alejandre
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: Laura
authors.initials: L
authors.lastname: Sanz
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Martina
authors.initials: M
authors.lastname: Sigal
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT, Australia 2601;
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Spillman
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Medicines for Malaria Venture, International Center Cointrin, 1215 Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: Spencer
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Anang
authors.initials: A
authors.lastname: Shelat
authors.affiliation: Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, QLD, Australia 4111;
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia 3052;
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA 94025;
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
authors.affiliation: Departments of Mechanical Engineering and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors.forename: Hongshen
authors.initials: H
authors.lastname: Ma
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT, Australia 2601;
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
authors.affiliation: Tres Cantos Medicines Development Campus-Diseases of the Developing World, GlaxoSmithKline, Tres Cantos 28760, Madrid, Spain;
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, FL 33612;
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2330;
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Floyd
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105; kip.guy@stjude.org.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000187:drug effects; D055808:Drug Discovery; D004351:Drug Resistance / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D010961:Plasmodium / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; C000597341:SJ733; D000252:Calcium-Transporting ATPases
keywords: PfATP4; drug discovery; malaria