| Autor: |
Ssemaganda A; Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. michael.good@griffith.edu.au d.stanisic@griffith.edu.au s.berners-price@griffith.edu.au., Low LM; Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. michael.good@griffith.edu.au d.stanisic@griffith.edu.au s.berners-price@griffith.edu.au., Verhoeft KR; Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. michael.good@griffith.edu.au d.stanisic@griffith.edu.au s.berners-price@griffith.edu.au., Wambuzi M; UVRI-IAVI HIV Vaccine Program, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda., Kawoozo B; UVRI-IAVI HIV Vaccine Program, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda., Nabasumba SB; UVRI-IAVI HIV Vaccine Program, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda., Mpendo J; UVRI-IAVI HIV Vaccine Program, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda., Bagaya BS; UVRI-IAVI HIV Vaccine Program, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda and Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, P.O. Box 7072, Kampala, Uganda., Kiwanuka N; UVRI-IAVI HIV Vaccine Program, Uganda Virus Research Institute, P.O. Box 49, Entebbe, Uganda., Stanisic DI; Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. michael.good@griffith.edu.au d.stanisic@griffith.edu.au s.berners-price@griffith.edu.au., Berners-Price SJ; Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. michael.good@griffith.edu.au d.stanisic@griffith.edu.au s.berners-price@griffith.edu.au., Good MF; Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. michael.good@griffith.edu.au d.stanisic@griffith.edu.au s.berners-price@griffith.edu.au. |
| Abstrakt: |
Here, the anti-malarial activity 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 microscopically detectable parastiemia following inoculation which subsequently cleared. Following 1 or 3 doses of gold compound-treated parasitized red blood cells (pRBCs), protection was not observed when these mice were subsequently challenged with wild type P. chabaudi AS. In experiments where microscopically detectable parasites were observed following in vivo inoculation, mice were subsequently fully protected against a challenge infection with wildtype 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. |
