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

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Nawaratna, Sujeevi SK
McManus, Donald P
Gasser, Robin B
Brindley, Paul J
Boyle, Glen M
Rivera, Vanessa
Ranasinghe, Shiwanthi L
Jones, Malcolm K
You, Hong
Gobert, Geoffrey N
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2020
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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.

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Parasitology

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© 2020 Cambridge University Press. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.

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Veterinary sciences

Medical microbiology

1Naphthyl PP1

CaMK

CaMKII

STSP

Schistosoma mansoni

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Nawaratna, SSK; McManus, DP; Gasser, RB; Brindley, PJ; Boyle, GM; Rivera, V; Ranasinghe, SL; Jones, MK; You, H; Gobert, GN, Use of kinase inhibitors against schistosomes to improve and broaden praziquantel efficacy., Parasitology, 2020

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