biostudies-literatureJimenez-Diaz MBNIBIB NIH HHSHoward Hughes Medical InstituteNIAID NIH HHSNCI NIH HHSHoward Hughes Medical Institute (HHMI)PHS HHSNIGMS NIH HHSHHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)E5455-62https://www.ebi.ac.uk/biostudies/studies/S-EPMC4273362biostudies-literatureUnknown111(50)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 incrProceedings of the National Academy of Sciences of the United States of America(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.PMC4273362HHSN272201100022IP30 CA021765NAT32 GM067547AI090662HHSN272201100022CR01 AI090662U01 AI075517HHSN2722011000221T32 EB009383AI075517Kim CCDuffy SMirsalis JCClark JAJimenez-Diaz MBO'Loughlin KGHolbrook GFerrer SMatheny AWang ZDeng XGuy RKPradhan AEbert DAvery VMLee MCCharman SAGomez MGKyle DEAngulo-Barturen IDiep JMartinez MSFedewa GLiu JKnapp SDennis ASSalinas YMiller GFidock DASanz LSpillman NJWaterson DLehane AMHorst JGuiguemde WAKirk KGamo FJRodriguez-Alejandre ADeRisi JLMyrand-Lapierre MEJustino de Almeida MFloyd DMEndsley ANSigal MStein PDShackleford DMZhu FCarrillo AKShelat AMa Hfalse(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.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 incr2014-01-01T00:00:00Z2014 Dec2026-04-16T21:28:36.868Z2019-03-27T01:42:11ZS-EPMC42733622545309110.1073/pnas.1414221111