Schistosome Sulfotransferases: Mode of Action, Expression and Localization

Abstract

Oxamniquine (OXA) is a prodrug activated by a sulfotransferase (SULT) that was only active against Schistosoma mansoni. We have reengineered OXA to be effective against S. haematobium and S. japonicum. Three derivatives stand out, CIDD-0066790, CIDD-0072229, and CIDD-0149830 as they kill all three major human schistosome species. However, questions remain. Is the OXA mode of action conserved in derivatives? RNA-interference experiments demonstrate that knockdown of the SmSULT, ShSULT, and SjSULT results in resistance to CIDD-0066790. Confirming that the OXA-derivative mode of action is conserved. Next is the level of expression of the schistosome SULTs in each species, as well as changes in SULT expression throughout development in S. mansoni. Using multiple tools, our data show that SmSULT has higher expression compared to ShSULT and SjSULT. Third, is the localization of SULT in the adult, multicellular eucaryotic schistosome species. We utilized fluorescence in situ hybridization and uptake of radiolabeled OXA to determine that multiple cell types throughout the adult schistosome worm express SULT. Thus, we hypothesize the ability of many cells to express the sulfotransferase accounts for the ability of the OXA derivatives to kill adult worms. Our studies demonstrate that the OXA derivatives are able to kill all three human schistosome species and thus will be a useful complement to PZQ.

Oxamniquine derivatives overcome Praziquantel treatment limitations for Schistosomiasis

“…This might be associated with the level of Sm SULT transcript. The expression of Sm SULT in male worms increases in 21 dpi, 28 dpi reaching the highest levels at day 35 dpi [ 36 – 38 ]. Similar to male worms, female worms’ Sm SULT transcript increases in 21 dpi, peaks at day 28 dpi, but then begins to decrease [ 36 , 37 ].…”

“…Thus, we anticipate the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Our studies demonstrated that OXA derivative 790 has the same mode of action as OXA [ 38 ]. Knockdown of Sm SULT using RNA-interference ( S2 Fig ) results in resistance to 830 , 610 and 303 treatments, confirming that the mode of action is conserved.…”

“…The worms were observed for 14 days. Observation included notes on worm health, viability; lack of motility, shedding of tegument, blebbing of tegument, internal vacuolization, lethargy, and being opaque [ 38 ].…”

Computer-Assisted Discovery of Salvia fruticosa Compounds With Schistosomicidal Activity

“…Studies have identified Schistosoma mansoni sulfotransferase ( Sm SULT) to be one of the attractive drug targets for rational drug design to treat schistosomiasis. 28 , 29 Sulfotransferases catalyse the transfer of a sulfuryl group from a sulphate donor to substrates. 29 Therefore, inhibition of the Sm SULT is fatal to the organism.…”

“… 28 , 29 Sulfotransferases catalyse the transfer of a sulfuryl group from a sulphate donor to substrates. 29 Therefore, inhibition of the Sm SULT is fatal to the organism. The past effectiveness of oxamniquine against S mansoni infections in Brazil has validated Sm SULT as a viable drug target.…”