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dc.contributor.authorBelen Jimenez-Diaz, Maria
dc.contributor.authorEbert, Daniel
dc.contributor.authorSalinas, Yandira
dc.contributor.authorPradhan, Anupam
dc.contributor.authorLehane, Adele M
dc.contributor.authorMyrand-Lapierre, Marie-Eve
dc.contributor.authorO'Loughlin, Kathleen G
dc.contributor.authorShackleford, David M
dc.contributor.authorde Almeida, Mariana Justino
dc.contributor.authorCarrillo, Angela K
dc.contributor.authorClark, Julie A
dc.contributor.authorDennis, Adelaide SM
dc.contributor.authorDiep, Jonathon
dc.contributor.authorDeng, Xiaoyan
dc.contributor.authorDuffy, Sandra
dc.contributor.authorEndsley, Aaron N
dc.contributor.authorFedewa, Greg
dc.contributor.authorGuiguemde, W Armand
dc.contributor.authorGomez, Maria G
dc.contributor.authorHolbrook, Gloria
dc.contributor.authorHorst, Jeremy
dc.contributor.authorKim, Charles C
dc.contributor.authorLiu, Jian
dc.contributor.authorLee, Marcus CS
dc.contributor.authorMatheny, Amy
dc.contributor.authorSantos Martinez, Maria
dc.contributor.authorMiller, Gregory
dc.contributor.authorRodriguez-Alejandre, Ane
dc.contributor.authorSanz, Laura
dc.contributor.authorSigal, Martina
dc.contributor.authorSpillman, Natalie J
dc.contributor.authorStein, Philip D
dc.contributor.authorWang, Zheng
dc.contributor.authorZhu, Fangyi
dc.contributor.authorWaterson, David
dc.contributor.authorKnapp, Spencer
dc.contributor.authorShelat, Anang
dc.contributor.authorAvery, Vicky M
dc.contributor.authorFidock, David A
dc.contributor.authorGamo, Francisco-Javier
dc.contributor.authorCharman, Susan A
dc.contributor.authorMirsalis, Jon C
dc.contributor.authorMa, Hongshen
dc.contributor.authorFerrer, Santiago
dc.contributor.authorKirk, Kiaran
dc.contributor.authorAngulo-Barturen, Inigo
dc.contributor.authorKyle, Dennis E
dc.contributor.authorDeRisi, Joseph L
dc.contributor.authorFloyd, David M
dc.contributor.authorGuy, R Kiplin
dc.contributor.editorInder M. Verma
dc.date.accessioned2018-04-30T12:00:20Z
dc.date.available2018-04-30T12:00:20Z
dc.date.issued2014
dc.identifier.issn0027-8424
dc.identifier.doi10.1073/pnas.1414221111
dc.identifier.urihttp://hdl.handle.net/10072/140665
dc.description.abstractDrug 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNational Academy of Sciences
dc.publisher.placeUnited States
dc.relation.ispartofpagefromE5455
dc.relation.ispartofpagetoE5462
dc.relation.ispartofissue50
dc.relation.ispartofjournalNational Academy of Sciences. Proceedings (PNAS)
dc.relation.ispartofvolume111
dc.subject.fieldofresearchMicrobiology not elsewhere classified
dc.subject.fieldofresearchcode310799
dc.title(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorDuffy, Sandra
gro.griffith.authorAvery, Vicky M.


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