Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

Sundaraneedi, Madhu K., Tedla, Bemnet A., Eichenberger, Ramon M., Becker, Luke, Pickering, Darren, Smout, Michael J., Rajan, Siji, Wangchuk, Phurpa, Keene, F. Richard, Loukas, Alex, Collins, J. Grant, and Pearson, Mark S. (2017) Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases. PLoS Neglected Tropical Diseases, 11 (12). e0006134.

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Schistosomiasis is a neglected tropical disease which affects over 200 million people and there is only one licensed drug, praziquantel, currently available for treatment. In a search for new drugs to control schistosomiasis, we tested the anti-schistosome efficacy of a series of ruthenium compounds and found that a number of them were able to inhibit parasite eggs from hatching and kill adult worms and praziquantel-refractory juvenile worms in vitro. We demonstrated that the compounds inhibit schistosome acetylcholinesterase (the enzyme that breaks down the neurotransmitter acetylcholine), which could potentially result in paralysis of the parasite, likely due to uncontrolled neuromuscular function caused by acetylcholine excess. Moreover, we showed that drug treated worms had a significantly reduced ability to uptake exogenous glucose and markedly depleted glycogen stores, presumably through inhibition of the acetylcholinesterase-mediated glucose scavenging pathway. Lastly, we found that two of the drugs— Rubb -tri and Rubb -tnl—when used to treat schistosome-infected mice, were able to reduce worm burdens and significantly affect the viability of parasite eggs in vivo, which would have a marked impact on disease transmission. We believe that these complexes are desirable drug lead scaffolds which could be used to develop effective and selective compounds to control and treat schistosomiasis and, potentially, other parasitic diseases.

Item ID: 52661
Item Type: Article (Research - C1)
ISSN: 1935-2735
Keywords: Schistosomiasis; ruthenium complexes; acetylcholinesterase
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© 2017 Sundaraneedi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funders: National Health and Medical Research Council of Australia (NHMRC), University of New South Wales, James Cook University
Projects and Grants: NHMRC Grant APP1132975
Date Deposited: 25 Feb 2018 23:40
FoR Codes: 34 CHEMICAL SCIENCES > 3402 Inorganic chemistry > 340201 Bioinorganic chemistry @ 20%
42 HEALTH SCIENCES > 4206 Public health > 420605 Preventative health care @ 30%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3207 Medical microbiology > 320704 Medical parasitology @ 50%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 70%
97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 30%
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