Rational approach to drug discovery for human schistosomiasis

Abstract

Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma , praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes.

Schistosome Sulfotransferases: Mode of Action, Expression and Localization

“…Using RNAi, silencing of the sulfotransferase in each species resulted in resistance to the OXA derivative and reinforced the notion that the mechanism of killing was the result of sulfation of CIDD-0066790 (Figures 2-4). Evidence to date suggests that the ability of OXA, or its derivatives, to fit into the binding pocket and accept the transfer of a sulfur group from a sulfur donor is more likely the reason for activation and subsequent killing ability [24,25,29].…”

“…Where and to what extent is the SULT expressed in the adult parasite and does this account for the mechanism of killing? We used CIDD-0066790 for these studies as it will kill all three human species of Schistosoma [ 25 ].…”

“…Previous studies demonstrated a stage-specific susceptibility of S. mansoni to OXA treatment [ 12 , 38 ]. Now that the mechanism of action of OXA has been elucidated [ 21 , 25 ], the expression of SULT can be correlated with OXA killing ( Figure 5 and Figure 6 ). Interestingly, at the infectious cercariae stage, the cercarial tail expresses higher levels of SmSULT than the cercarial head.…”

“…Sulfotransferases are enzymes that catalyze the transfer of a sulfuryl group (SO 3 ) from a sulfate donor, such as 3′-phosphoadenosine 5′-phosphosulfate (PAPS), to substrates. Activated OXA binds to DNA and other macromolecules, resulting in the killing of the schistosome adult worms [ 21 , 23 , 24 , 25 ]. This affects both adult sexes but mainly males, causing the parasite to detach from the hepatoportal circulation and move into the liver where they are eliminated.…”

In Silico Study of Cucurbita maxima Compounds as Potential Therapeutics Against Schistosomiasis

“…An interesting iterative drug development process successfully identified derivatives of the OXA drug that are effective against all three species of the Schistosoma parasite. 40 Evaluation of 6-Gingerol and its modified analogues as therapeutic candidates against S. mansoni phosphofructokinase 41 , 42 has also been done. Molecular docking methods showed oxadiazole-2-oxides derivatives furoxan exhibiting significant anti-schistosomal activity against S. japonicum .…”