Authors

Discussion

Schistosomiasis is a neglected tropical disease (NTD) that currently affects over 230 million people in subtropical and tropical regions with a further 779 million people at risk of becoming infected globally. Schistosoma mansoni is one of the three major parasitic trematodes that causes schistosomiasis, with 54 million people infected annually with this species. Praziquantel is known to be the only drug recommended by the (WHO) for the treatment and control of all Schistosoma species worldwide, however, there is evidence suggesting that resistance is indeed a possibility.

In the absence of a vaccine, and to prepare for praziquantel resistant, new chemical matter needs to be brought into the drug discovery pipeline to sustain schistosomiasis control.

SPHK, is an enzyme that phosphorylate sphingolipid sphingosine to produced sphingosine 1 phosphate (S1P). S1P regulates various cellular processes and survival of the parasite when in the host. Dysregulation of SPHK and S1P signalling has been implicated in several diseases, including cancer, inflammation, and autoimmune disorders. Understanding how schistosoma mansoni parasites are affected by inhibiting Sphk1 provides insights into potential drug targets for treatment against schistosomiasis

SPHK1 Inhibitors were screened against adult worm pairs (50 µM) followed by dose response titration (25 µM, 12.5 µM, and 6.25 µM) with phenotypic scoring conducted at 24, 48, and 72 hours using the WHO-TDR scoring matrix. Worm death, motility effect and egg production effects were observed.

Determined from BLASTp interrogations, the likely target of these SPHK1 inhibitors is Smp_157100, a S. mansoni protein that contains conserved amino acid residues to those found in critical positions within the human functional homologue.

Moving forward, additional phenotypic screens using chemical analogues of the most potent SPHK inhibitor will be performed as well as SPHK activity in S. mansoni will be measured in adult worms treated with the SPHK inhibitors compared to controls. Confirmation of these results in adults will be performed using an antibody (S1P antibody) that detects phosphorylated sphingosine (S1P). Additionally, Long-term culture of the worms treated with compounds will be performed to observe the occurring effects upon worm development. Finally, RNAi will be used to knock-down smp_157100 to provide further support that SPHK is essential to S. mansoni. The results of these experiments will provide complementary evidence for progressing SPHK as an urgently needed novel drug target for schistosomiasis.