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Use of kinase inhibitors against schistosomes to improve and broaden praziquantel efficacy

Published online by Cambridge University Press:  03 August 2020

Sujeevi S. K. Nawaratna ,
Donald P. McManus Open the ORCID record for Donald P. McManus [Opens in a new window] ,
Robin B. Gasser ,
Paul J. Brindley ,
Glen M. Boyle ,
Vanessa Rivera ,
Shiwanthi L. Ranasinghe ,
Malcolm K. Jones Open the ORCID record for Malcolm K. Jones [Opens in a new window] ,
Hong You Open the ORCID record for Hong You [Opens in a new window]  and
Geoffrey N. Gobert
Sujeevi S. K. Nawaratna
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia School of Medicine, Griffith University, Gold Coast, Australia
Donald P. McManus
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Robin B. Gasser
Affiliation:
Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Australia
Paul J. Brindley
Affiliation:
School of Medicine and Health Sciences, George Washington University, WashingtonDC, USA
Glen M. Boyle
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Vanessa Rivera
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia School of Medicine, Deakin University, Geelong, Australia
Shiwanthi L. Ranasinghe
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Malcolm K. Jones
Affiliation:
School of Veterinary Science, The University of Queensland, Gatton, Australia
Hong You*
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia
Geoffrey N. Gobert*
Affiliation:
QIMR Berghofer Medical Research Institute, Herston, Australia School of Biological Sciences, Queen's University Belfast, Belfast, UK
*
Author for correspondence: Geoffrey N. Gobert, E-mail: [email protected]; Hong You, E-mail: [email protected]
Author for correspondence: Geoffrey N. Gobert, E-mail: [email protected]; Hong You, E-mail: [email protected]
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Abstract

Praziquantel (PZQ) is the drug of choice for schistosomiasis. The potential drug resistance necessitates the search for adjunct or alternative therapies to PZQ. Previous functional genomics has shown that RNAi inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) gene in Schistosoma adult worms significantly improved the effectiveness of PZQ. Here we tested the in vitro efficacy of 15 selective and non-selective CaMK inhibitors against Schistosoma mansoni and showed that PZQ efficacy was improved against refractory juvenile parasites when combined with these CaMK inhibitors. By measuring CaMK activity and the mobility of adult S. mansoni, we identified two non-selective CaMK inhibitors, Staurosporine (STSP) and 1Naphthyl PP1 (1NAPP1), as promising candidates for further study. The impact of STSP and 1NAPP1 was investigated in mice infected with S. mansoni in the presence or absence of a sub-lethal dose of PZQ against 2- and 7-day-old schistosomula and adults. Treatment with STSP/PZQ induced a significant (47–68%) liver egg burden reduction compared with mice treated with PZQ alone. The findings indicate that the combination of STSP and PZQ dosages significantly improved anti-schistosomal activity compared to PZQ alone, demonstrating the potential of selective and non-selective CaMK/kinase inhibitors as a combination therapy with PZQ in treating schistosomiasis.

Keywords

1Naphthyl PP1adjunct therapyCaMKCaMKIIkinase inhibitorspraziquantelSchistosoma mansonischistosomulaStaurosporineSTSP
Type
Research Article
Information
Parasitology , Volume 147 , Issue 13 , November 2020 , pp. 1488 - 1498
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Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

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Footnotes

*

These authors contributed equally.

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