Genetic complementation analysis of two independently isolated hycanthone-resistant strains of Schistosoma mansoni

The objective of this study is to determine whether various hycanthone resistant strains of schistosomes which have been independently isolated are all affected in the same gene. A strain obtained from a Brazilian patient was compared with a strain of Puerto Rican origin selected in the laboratory. If the mutation conferring resistance involved two different genes, one would expect that the progeny of a cross between the two strains would show complementation, i.e. it would be sensitive to the drug. We have performed such a cross and obtained F1 hybrid worms wich were essentially all resistant, thus suggesting that the mutation conferring resistance in the two strains involves the same gene

The schistosome enzyme that activates oxamniquine has the characteristics of a sulfotransferase

Available evidence suggests that the antischistosomal drug oxamniquine is converted to a reactive ester by a schistosome enzyme that is missing in drug-resistant parasites. This study presents data supporting the idea that the active ester is a sulfate and the activating enzyme is a sulfotransferase. Evidence comes from the fact that the parasite extract loses its activating capability upon dialysis, implying the requirement of some dialyzable cofactor. The addition of the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) restored activity of the dialyzate, a strong indication that a sulfotransferase is probably involved. Classical sulfotransferase substrates like b-estradiol and quercetin competitively inhibited the activation of oxamniquine. Furthermore, these substrates could be sulfonated in vitro using an extract of sensitive (but not resistant) schistosomes. Gel filtration analysis showed that the activating factor eluted in a fraction corresponding to a molecular mass of about 32 kDa, which is the average size of typical sulfotransferase subunits. Ion exchange and affinity chromatography confirmed the sulfotransferase nature of the enzyme. Putative sulfotransferases present in schistosome databases are being examined for their possible role as oxamniquine activators

Synthesis and antischistosomal activity of new furoxan derivatives of praziquantel

112-119A series of new furoxan derivatives of praziquantel have been synthesized and evaluated for antischistosomal activity. The newly synthesized hybrid compounds have structural modifications at amide and aromatic rings and thus offer broad structure-activity variations. All the compounds have been tested against adult as well as immature Schistosoma mansoni. Compounds 15 and 18 show moderate activity against adult schistosomes. On immature worms, only compound 15 shows substantial activity whereas the standard drug PZQ is practically inactive at this stage

Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine - Fig 2

<p><b>A) Separation of oxamniquine stereoisomers by HPLC on a chiral column.</b> B) HPLC purity control on the same column of a pool of fractions # 1 obtained from several runs like the one depicted in A. C) HPLC purity control on the same column of a pool of fractions # 2 obtained from several runs like the one depicted in A.</p