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

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.

Drug resistant parasites and fungi from a one-health perspective: A global concern that needs transdisciplinary stewardship programs

“…can infect humans and animals. Thus, the appearance of Echinococcus resistant strains to praziquantel would pose a major health concern considering the risk for an increase in human larval echinococcosis and resistance, and required new therapeutic approaches including the use of adjuvant to improve praziquantel efficacy [ 27 ]. Albendazole is the most efficient and safe drug to interrupt larval growth of Echinococcus spp [ 28 , 29 ] without evidence of resistance, leading to its use as a first-line anti-infective treatment for alveolar and cystic echinococcosis [ 28 ].…”

Protein Kinases: Potential Drug Targets Against Schistosoma japonicum

“…In S. japonicum , a similar calcium pathway may also exist, underlaying future research about the interaction between CAMKII and schistosomes. Another study applied selective and nonselective CAMK/Kinase inhibitors including 1Naphthyl PP1 (1NAPP1) and Staurosporine (STSP) in schistosomes with or without the presence of PZQ in vivo and in vitro ( Nawaratna et al., 2020 ). The results showing that the combination of PZQ and 1NAPP1 treatment is more effective to kill 7-day old schistosomula and weaken the motility of adult worms ( Nawaratna et al., 2020 ).…”

“…Another study applied selective and nonselective CAMK/Kinase inhibitors including 1Naphthyl PP1 (1NAPP1) and Staurosporine (STSP) in schistosomes with or without the presence of PZQ in vivo and in vitro ( Nawaratna et al., 2020 ). The results showing that the combination of PZQ and 1NAPP1 treatment is more effective to kill 7-day old schistosomula and weaken the motility of adult worms ( Nawaratna et al., 2020 ). However, only the group treated with the highest dose of STSP conjunction with PZQ exhibits the highest decrease in worms and eggs compared with the control group and thus significantly lower (58%) liver egg counts compared with the PZQ group in vivo ( Nawaratna et al., 2020 ).…”

“…The results showing that the combination of PZQ and 1NAPP1 treatment is more effective to kill 7-day old schistosomula and weaken the motility of adult worms ( Nawaratna et al., 2020 ). However, only the group treated with the highest dose of STSP conjunction with PZQ exhibits the highest decrease in worms and eggs compared with the control group and thus significantly lower (58%) liver egg counts compared with the PZQ group in vivo ( Nawaratna et al., 2020 ).…”

CaMKII regulates neuromuscular activity and survival of the human blood fluke Schistosoma mansoni

“…In adult S. japonicum, CaMKII gene expression was shown to increase following exposure to sub-lethal concentrations of PZQ, and suppression of CaMKII gene expression improved PZQ e cacy 19 . More recently, in S. mansoni, PZQ e cacy improved against normally refractory juvenile parasites when they were co-treated with non-selective CaMK inhibitors 20 Recently we undertook a deep phosphoproteomic analysis of S. mansoni adult worms and discovered that CaMKII phosphorylation motifs were highly represented in the dataset, highlighting the likely importance of this kinase in these worms 21 . Here we aimed to investigate in detail the S. mansoni CaMKII protein, functionally map the protein within human infective life stages of the parasite and determine the importance of CaMKII to S. mansoni homeostasis and survival.…”