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Gold(I) Phosphine Compounds as Parasite Attenuating Agents for Malaria Vaccine and Drug Development

Abstract

Here,the anti-malarial activities of two gold(I) phosphine compounds, auranofin and [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as potential drugs and malaria parasite-attenuating agents. In vitro, the gold compounds were active against Plasmodium falciparum and P. knowlesi as well as the rodent parasite P. chabaudi AS. Attenuation of the parasite was observed when mice were inoculated with P. chabaudi AS infected red blood cells treated in vitro with [Au(d2pype)2]Cl (1 or 2 μM) or auranofin (2 μM) for 2 or 3 h. Quantitative PCR data showed persistence of low levels of parasite DNA up to 8 days’ post inoculation. In some experiments, there was low level microscopically detectable parastiemia following inoculation which subsequently cleared. These mice were then immune to challenge infection with untreated parasites. In other experiments parasites were not detectable microscopically following inoculaton. These mice were not subsequently immune to challenge infection with untreated parasites. In an infect-and-treat rodent model, the gold compounds were unable to inhibit P. chabaudi AS growth in vivo when administered orally. Gold compounds act via the inhibition of antioxidant systems which are critical in the pathogen’s survival from attack by the host oxidants. In vitro, they directly inhibit the parasite thioredoxin reductase, hence the observed suppressive activity. On the other hand, in vivo, the gold compounds may not be readily available for absorption and thus pharmacokinetic studies will be required to further examine drug bioavailability following administration. With structural differences in redox mechanisms of P. falciparum and the human host being identified, gold compounds can be better designed to more efficiently target and selectively inhibit the parasite.

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Publication details

The article was received on 09 Nov 2017, accepted on 13 Feb 2018 and first published on 13 Feb 2018


Article type: Paper
DOI: 10.1039/C7MT00311K
Citation: Metallomics, 2018, Accepted Manuscript
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    Gold(I) Phosphine Compounds as Parasite Attenuating Agents for Malaria Vaccine and Drug Development

    A. Ssemaganda, L. M. Low, K. R. Verhoeft, M. Wambuzi, B. Kawoozo, S. B. Nabasumba, J. Mpendo, B. S. Bagaya , N. Kiwanuka, D. Stanisic, S. Berners-Price and M. F. Good, Metallomics, 2018, Accepted Manuscript , DOI: 10.1039/C7MT00311K

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