dc.contributor.author | Andrews, Kathy | |
dc.contributor.author | Fisher, Gillian | |
dc.contributor.author | Riches, Andrews | |
dc.contributor.author | Hutt, Oliver | |
dc.contributor.author | Jarvis, Karen | |
dc.contributor.author | Wilson, Tony | |
dc.contributor.author | von Itzstein, Mark | |
dc.contributor.author | Chopra, Pradeep | |
dc.contributor.author | Antonova-Koch, Yevgeniya | |
dc.contributor.author | Meister, Stephan | |
dc.contributor.author | Winzeler, Elizabeth | |
dc.contributor.author | Clarke, Mary | |
dc.contributor.author | Fidock, David | |
dc.contributor.author | Burrows, Jeremy | |
dc.contributor.author | Ryan, John | |
dc.contributor.author | Skinner-Adams, Tina | |
dc.date.accessioned | 2020-03-26T02:14:48Z | |
dc.date.available | 2020-03-26T02:14:48Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 0002-9637 | |
dc.identifier.doi | 10.4269/ajtmh.abstract2019 | |
dc.identifier.uri | http://hdl.handle.net/10072/392642 | |
dc.description.abstract | Malarone® is a combination of atovaquone and proguanil that is used for malaria prophylaxis and treatment. Atovaquone has potent antiplasmodium activity as a cytochrome bc1-inhibitor while dogma is that proguanil does not have potent intrinsic activity. Proguanil can, however, potentiate atovaquone activity and its cyclization-metabolite (cycloguanil) is a dihydrofolate reductase inhibitor with potent activity. We have recently found that proguanil, and an analogue that cannot convert to cycloguanil (tBuPG), have potent slow-acting activity in vitro against asexual P. falciparum parasites. This activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast DHODH-expressing parasites, proguanil and tBuPG slow action activity remains, however bc1- inhibitor activity switches from fast to slow-acting. Proguanil and tBuPG both act synergistically with bc1-inhibitors, while cycloguanil antagonizes activity. Overall, our data suggest that proguanil has potent slow-acting activity against asexual-stage P. falciparum, that bc1 is essential to parasite survival independent of DHODH-activity and that Malarone® may act as a triple-drug combination (including antagonistic partners). These findings raise the possibility that a cyclization-blocked proguanil may be a better in vivo combination partner for antimalarial bc1-inhibitors. | |
dc.language | English | |
dc.publisher | American Society of Tropical Medicine and Hygiene | |
dc.relation.ispartofconferencename | 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH) | |
dc.relation.ispartofconferencetitle | AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE | |
dc.relation.ispartofdatefrom | 2019-11-20 | |
dc.relation.ispartofdateto | 2019-11-24 | |
dc.relation.ispartoflocation | National Harbor, MD | |
dc.relation.ispartofpagefrom | 270 | |
dc.relation.ispartofpagefrom | 1 pages | |
dc.relation.ispartofpageto | 270 | |
dc.relation.ispartofpageto | 1 pages | |
dc.relation.ispartofvolume | 101 | |
dc.subject.fieldofresearch | Biomedical and clinical sciences | |
dc.subject.fieldofresearch | Medical microbiology | |
dc.subject.fieldofresearch | Health sciences | |
dc.subject.fieldofresearchcode | 32 | |
dc.subject.fieldofresearchcode | 3207 | |
dc.subject.fieldofresearchcode | 42 | |
dc.subject.keywords | Science & Technology | |
dc.subject.keywords | Life Sciences & Biomedicine | |
dc.subject.keywords | Public, Environmental & Occupational Health | |
dc.subject.keywords | Tropical Medicine | |
dc.title | New insights into the mode of action of the antimalarial drug proguanil | |
dc.type | Conference output | |
dc.type.description | E3 - Conferences (Extract Paper) | |
dcterms.bibliographicCitation | Andrews, K; Fisher, G; Riches, A; Hutt, O; Jarvis, K; Wilson, T; von Itzstein, M; Chopra, P; Antonova-Koch, Y; Meister, S; Winzeler, E; Clarke, M; Fidock, D; Burrows, J; Ryan, J; Skinner-Adams, T, New insights into the mode of action of the antimalarial drug proguanil, American Journal of Tropical Medicine and Hygiene, 2019, 101, pp. 270-270 | |
dc.date.updated | 2020-03-26T01:31:12Z | |
dc.description.version | Version of Record (VoR) | |
gro.rights.copyright | © 2019 American Society of Tropical Medicine and Hygiene. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version. | |
gro.hasfulltext | Full Text | |
gro.griffith.author | von Itzstein, Mark | |
gro.griffith.author | Skinner-Adams, Tina | |
gro.griffith.author | Fisher, Gill M. | |
gro.griffith.author | Andrews, Katherine T. | |