Protein Kinases: Potential Drug Targets Against Schistosoma japonicum

Abstract

Schistosoma japonicum (S. japonicum) infection can induce serious organ damage and cause schistosomiasis japonica which is mainly prevalent in Asia and currently one of the most seriously neglected tropical diseases. Treatment of schistosomiasis largely depends on the drug praziquantel (PZQ). However, PZQ exhibits low killing efficacy on juvenile worms and the potential emergence of its drug resistance is a continual concern. Protein kinases (PKs) are enzymes that catalyze the phosphorylation of proteins and can participate in many signaling pathways in vivo. Recent studies confirmed the essential roles of PKs in the growth and development of S. japonicum, as well as in schistosome-host interactions, and researches have screened drug targets about PKs from S. japonicum (SjPKs), which provide new opportunities of developing new treatments on schistosomiasis. The aim of this review is to present the current progress on SjPKs from classification, different functions and their potential to become drug targets compared with other schistosomes. The efficiency of related protein kinase inhibitors on schistosomes is highlighted. Finally, the current challenges and problems in the study of SjPKs are proposed, which can provide future guidance for developing anti-schistosomiasis drugs and vaccines.

Discovery of Schistosoma mekongi circulating proteins and antigens in infected mouse sera

“…Moreover, suppressor of cytokine signaling 7 may be involved in the suppression of host immune responses via the inhibition of cytokine-inducible activator of transcription-mediated signal transduction [88,89]. In schistosomes, protein kinase plays essential roles in growth, development, and host interaction; therefore, they have been considered as targets for drugs against parasitic diseases in many research efforts [90]. Serine/threonine protein phosphatases are important for the control of S. japonicum growth and reproduction [81], whereas cullin-3 is a core component of the E3 ubiquitin ligase complex and may play roles in the development of the reproductive organs of S. mekongi [24,91].…”

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part III: Helminths

“…Results revealed its essentiality for miracidia viability, schistosomula development and survival, adults pairing, and female maturation [28] . Wu et al [29] claimed in their review that Schistosoma TKs were identified in two types: receptors, and non-receptors (cytosolic TKs). The first included epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, with high tegumental transcriptional expression activity.…”

“…While SjIR-1 was mainly expressed in the tegument basal membrane and muscles, SjIR-2 was expressed in female vitelline tissue and male parenchyma. Therefore, to develop a safe drug utilizing SjIR inhibitors, it is important to explore their roles in relation to host IRs [29] .…”

“…Its transcription level was localized in the vitellarium and ovary, and its bioinformatics analysis revealed its high potentiality as drug target. The reviewers recommended further studies exploring AGC signaling pathways and functions, and claimed that combined application of CRISPR-Cas9 technology with virtual screening would accelerate development of novel antischistosomal drugs [29] .…”

“…The drug showed significant decrease in worm burden, intestinal and hepatic egg counts, and progressive reduction of viability of both juvenile and adult schistosomes [32] . Future studies to investigate other PKs inhibitors used as anti-cancer drugs in treatment of schistosomiasis japonicum were recommended including Genistein, Sorafenib, Bosutinib, Crizotinib, Nilotinib, and Dasatinib [29] . Notably, among 52 FDA-approved drugs, 21 are multikinase inhibitors [33] .…”