dc.contributor.author | Skinner-Adams, Tina S | |
dc.contributor.author | Fishers, Gillian M | |
dc.contributor.author | Riches, Andrew G | |
dc.contributor.author | Hutt, Oliver E | |
dc.contributor.author | Jarvis, Karen E | |
dc.contributor.author | Wilson, Tony | |
dc.contributor.author | von Ltzstein, Mark | |
dc.contributor.author | Chopra, Pradeep | |
dc.contributor.author | Antonova-Koch, Yevgeniya | |
dc.contributor.author | Meister, Stephan | |
dc.contributor.author | Winzeler, Elizabeth A | |
dc.contributor.author | Clarke, Mary | |
dc.contributor.author | Fidock, David A | |
dc.contributor.author | Burrows, Jeremy N | |
dc.contributor.author | Ryan, John H | |
dc.contributor.author | Andrews, Katherine T | |
dc.date.accessioned | 2019-09-27T03:50:29Z | |
dc.date.available | 2019-09-27T03:50:29Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 2399-3642 | |
dc.identifier.doi | 10.1038/s42003-019-0397-3 | |
dc.identifier.uri | http://hdl.handle.net/10072/387852 | |
dc.description.abstract | Atovaquone-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.peerreviewed | Yes | |
dc.description.sponsorship | Medicines for Malaria Venture | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Nature Publishing Group | |
dc.relation.ispartofissue | 1 | |
dc.relation.ispartofjournal | Communications Biology | |
dc.relation.ispartofvolume | 2 | |
dc.relation.uri | http://purl.org/au-research/grants/NHMRC/APP1071659 | |
dc.relation.uri | http://purl.org/au-research/grants/NHMRC/APP1098848 | |
dc.relation.grantID | APP1071659 | |
dc.relation.grantID | APP1098848 | |
dc.relation.funders | NHMRC | |
dc.subject.fieldofresearch | Biological sciences | |
dc.subject.fieldofresearch | Biomedical and clinical sciences | |
dc.subject.fieldofresearchcode | 31 | |
dc.subject.fieldofresearchcode | 32 | |
dc.subject.keywords | Science & Technology | |
dc.subject.keywords | Life Sciences & Biomedicine | |
dc.subject.keywords | Biology | |
dc.subject.keywords | Multidisciplinary Sciences | |
dc.subject.keywords | Life Sciences & Biomedicine - Other Topics | |
dc.title | Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dcterms.bibliographicCitation | Skinner-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.dateAccepted | 2019-03-15 | |
dcterms.license | http://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2019-09-27T03:47:47Z | |
dc.description.version | Version 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.hasfulltext | Full Text | |
gro.griffith.author | Skinner-Adams, Tina | |
gro.griffith.author | von Itzstein, Mark | |
gro.griffith.author | Andrews, Katherine T. | |
gro.griffith.author | Fisher, Gill M. | |