Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy

Abstract

The antischistosomal prodrug oxamniquine is activated by a sulfotransferase (SULT) in the parasitic flatworm Of the three main human schistosome species, only is sensitive to oxamniquine therapy despite the presence of SULT orthologs in and The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of and SULTs, including SULT in complex with oxamniquine. We also examined the activity of the three enzymes ; surprisingly, all three are active toward oxamniquine, yet we observed differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results provide guidance for designing oxamniquine derivatives to treat infection caused by all species of schistosome to combat emerging resistance to current therapy.

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

“…In 2015, Taylor et al. showed that the sulfotransferase of S. mansoni preferentially binds to the S enantiomer of 13 (Figure B) due to its better steric fit into the central cavity of the protein . Oxidation of the hydroxymethyl group leads to 6‐formyl‐oxamniquine ( 17 , Figure D), which has a similar antischistosomal activity.…”

“…[10] In 2015, Ta ylor et al showed that the sulfotransferase of S. mansoni preferentially binds to the S enantiomer of 13 ( Figure 3B)d ue to its betters teric fit into the central cavity of the protein. [93,94] Oxidation of the hydroxymethyl group leads to 6-formyl-oxamniquine (17,F igure 3D), which has asimilar antischistosomal activity.This is explained by the re-reduction of the aldehyde either by human or parasite reductases. [95] The other major metabolites of 13 (18 and 19,F igure 3D)p resented no negative effects.…”

An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

“…single gene are responsible for both HYC and OXA resistance [20] which has developed in the field [21,22] and has been selected for in the laboratory [23]. The mechanism of OXA activity and the mechanism for OXA resistance were identified by further genetic and crystallographic studies [24,25]. OXA and HYC are prodrugs that are enzymatically activated in the parasite [24][25][26][27][28].…”

“…The mechanism of OXA activity and the mechanism for OXA resistance were identified by further genetic and crystallographic studies [24,25]. OXA and HYC are prodrugs that are enzymatically activated in the parasite [24][25][26][27][28]. OXA binds to a specific S. mansoni sulfotransferase, known as SmSULT-OR, where it is transiently sulfated.…”

“…The sulfur group on the released sulfate ester undergoes a nucleophilic attack by schistosome macromolecules. In an S N 2-like reaction, activated OXA forms adducts with DNA and other macromolecules, resulting in killing of the worms [24,25]. This affects both adult sexes but mainly the males, causing the parasites to detach from hepatoportal circulation and move into the liver where they are eliminated, in part, by the formation of an adduct on DNA thus blocking DNA replication and transcription [25,27,29].…”