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Cover for Analysis of Parasite Chloroquine Resistance Transporter Proteins and Their Roles in Drug Resistance Phenomena
dc.contributor.advisorRoepe, Paul D
dc.creator
dc.date.accessioned2020-06-30T12:51:15Z
dc.date.created2020
dc.date.issued
dc.date.submitted01/01/2020
dc.identifier.uri
dc.descriptionPh.D.
dc.description.abstractThe development of drug resistance in Plasmodium parasites continues to present a major challenge in abating the global malaria burden. It has been well established that mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) are critical determining factors in quinoline antimalarial drug resistance mechanisms. Our best understanding of this mechanism implicates CRT-facilitated downhill leak of chloroquine (CQ) out of the parasite digestive vacuole – the site of action for CQ. At least 53 distinct PfCRT isoforms are expressed in various P. falciparum isolates around the globe. Previous work characterized the altered CQ-transport conferring abilities of these isoforms heterologously expressed in yeast. Findings indicated that mutations in PfCRT were necessary, but not sufficient, for imparting chloroquine resistance (CQR) in parasite isolates expressing these isoforms. CQR is not as well characterized in P. vivax malaria. Accumulation of multiple mutations in PfCRT controls CQR for P. falciparum, however the role of novel single amino acid substitutions for the P. vivax orthologue (PvCRT) has not previously been examined. Relatedly, novel mutations recently found in PfCRT have been hypothesized to mediate resistance to piperaquine (PPQR), which is currently spreading in Southeast Asia, but whether these mutations affect CRT mediated drug transport has not been examined until now.
dc.description.abstractIn this thesis, I measure drug transport efficiencies of multiple PvCRT isoforms heterologously expressed in yeast. I also measure drug transport for novel PPQR-associated PfCRT isoforms, and test whether an orthologue of PfCRT found in the closely related apicomplexan parasite Toxoplasma gondii (TgCRT), is a functional transporter of CQ, as part of a broader investigation of the role of TgCRT in the endolysosomal system of T. gondii.
dc.description.abstractCurrently, artemisinin combination therapies (ACTs) represent front-line treatment for falciparum malaria. Unfortunately, a delayed clearance phenotype associated with reduced artemisinin efficacy has been identified, and reports of dihydroartemisinin/PPQ ACT treatment failure have been widely reported in Southeast Asia. Data presented for PPQR-associated PfCRT isoforms is discussed in the context of increasing failure of this ACT. Since some ACTs are becoming compromised, I also describe work with P. falciparum PI3K (PfVps34), which represents a novel target for much-needed new ACT partner drugs.
dc.formatPDF
dc.format.extent222 leaves
dc.languageen
dc.publisherGeorgetown University
dc.sourceGeorgetown University-Graduate School of Arts & Sciences
dc.sourceChemistry
dc.subjectArtemisinin
dc.subjectChloroquine
dc.subjectDrug resistance
dc.subjectMalaria
dc.subjectPfCRT
dc.subjectPiperaquine
dc.subject.lcshChemistry
dc.subject.lcshBiochemistry
dc.subject.lcshMolecular biology
dc.subject.otherChemistry
dc.subject.otherBiochemistry
dc.subject.otherMolecular biology
dc.titleAnalysis of Parasite Chloroquine Resistance Transporter Proteins and Their Roles in Drug Resistance Phenomena
dc.typethesis
gu.embargo.lift-date2020-12-30
gu.embargo.termscommon-6-months
dc.identifier.orcid0000-0002-1506-9671


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