Show simple item record

dc.contributor.authorSkinner-Adams, Tina S
dc.contributor.authorFishers, Gillian M
dc.contributor.authorRiches, Andrew G
dc.contributor.authorHutt, Oliver E
dc.contributor.authorJarvis, Karen E
dc.contributor.authorWilson, Tony
dc.contributor.authorvon Ltzstein, Mark
dc.contributor.authorChopra, Pradeep
dc.contributor.authorAntonova-Koch, Yevgeniya
dc.contributor.authorMeister, Stephan
dc.contributor.authorWinzeler, Elizabeth A
dc.contributor.authorClarke, Mary
dc.contributor.authorFidock, David A
dc.contributor.authorBurrows, Jeremy N
dc.contributor.authorRyan, John H
dc.contributor.authorAndrews, Katherine T
dc.date.accessioned2019-09-27T03:50:29Z
dc.date.available2019-09-27T03:50:29Z
dc.date.issued2019
dc.identifier.issn2399-3642
dc.identifier.doi10.1038/s42003-019-0397-3
dc.identifier.urihttp://hdl.handle.net/10072/387852
dc.description.abstractAtovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil’s action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against P. berghei liver-stage parasites. Both analogues act synergistically with bc1-inhibitors against blood-stages in vitro, however cycloguanil antagonizes activity. Together, these data suggest that proguanil is a potent slow-acting anti-plasmodial agent, that bc1 is essential to parasite survival independent of dihydroorotate dehydrogenase-activity, that Malarone® is a triple-drug combination that includes antagonistic partners and that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors in vivo.
dc.description.peerreviewedYes
dc.description.sponsorshipMedicines for Malaria Venture
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofissue1
dc.relation.ispartofjournalCommunications Biology
dc.relation.ispartofvolume2
dc.relation.urihttp://purl.org/au-research/grants/NHMRC/APP1071659
dc.relation.urihttp://purl.org/au-research/grants/NHMRC/APP1098848
dc.relation.grantIDAPP1071659
dc.relation.grantIDAPP1098848
dc.relation.fundersNHMRC
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode32
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiology
dc.subject.keywordsMultidisciplinary Sciences
dc.subject.keywordsLife Sciences & Biomedicine - Other Topics
dc.titleCyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationSkinner-Adams, TS; Fishers, GM; Riches, AG; Hutt, OE; Jarvis, KE; Wilson, T; von Ltzstein, M; Chopra, P; Antonova-Koch, Y; Meister, S; Winzeler, EA; Clarke, M; Fidock, DA; Burrows, JN; Ryan, JH; Andrews, KT, Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone, Communications Biology, 2019, 2 (1)
dcterms.dateAccepted2019-03-15
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2019-09-27T03:47:47Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
gro.hasfulltextFull Text
gro.griffith.authorSkinner-Adams, Tina
gro.griffith.authorvon Itzstein, Mark
gro.griffith.authorAndrews, Katherine T.
gro.griffith.authorFisher, Gill M.


Files in this item

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record