A new series of schistosomicide drugs, the alkylaminoalkanethiosulfuric acids, partially inhibit the activity of Schistosoma mansoni ATP diphosphohydrolase.
The effects of the alkylaminoalkanethiosulfuric acids (AAATs), new schistosomicidal drugs, on Schistosoma mansoni ATP diphosphohydrolase isoforms, members of the NTPDase family, were analyzed. Pre-incubation of worm adult tegument with AAATs derivatives, with small apolar alkyl groups and an apolar alkane portion of 6 or 8 carbon atoms linked to the amino group, inhibited ATPase activity with a Ki 100-1000 microM. Little inhibition (20%) was observed when ADP was the substrate. The 2-[(tert-butyl)amino]-1-ethanethiosulfuric acid (100 microM) which has a less lipophilic structure, inhibited 28% ATPase and 12% ADPase activities, suggesting that the lipophilicity, although important, is not the only requisite for enzyme activity inhibition. The N-(sec-butyl)-2-bromo-1-octanaminium bromide, which contains a bromide atom instead of thiosulphate, inhibited <10% of the enzyme activity, suggesting the involvement of cysteine residue(s) from S. mansoni ATP diphosphohydrolase isoforms in a mixed disulfide formation. Treatment of parasite tegument with 5 mM iodoacetamide or 1 mM dithiothreitol protected ATPase and ADPase activities against inhibition by AAATs, corroborating the participation of disulfide interchange in the AAATs mechanism. Since S. mansoni ATP diphosphohydrolase isoforms and potato apyrase share structural similarities, the latter enzyme was also tested. ADPase activity from potato apyrase was inhibited by 55%, showing a higher sensitivity to 1 mM AAATs than that shown by ADPase activity from the tegument, while the ATPase activities from both samples showed similar inhibition levels. Furthermore, sulfhydryl reagents protected potato apyrase activity. Therefore, it is possible that both soluble S. mansoni ATP diphosphohydrolase and membrane-associated isoforms are targets for the AAATs.
Luiz Oliveira Penido
Marcus
M
Departamento de Bioquímica/ICB, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil.
Resende
Dayse Moura
DM
Vianello
Marco Aurélio
MA
Humberto da Silveira Bordin
Fábio
F
Jacinto
Alexandre Arthur
AA
Dias
Walkyria Dutra
WD
Montesano
Maria Angela
MA
Nelson
David Lee
DL
Marcos Zech Coelho
Paulo
P
Vasconcelos
Eveline Gomes
EG
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001081:Apyrase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D007460:Iodoacetamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology; D012556:Schistosomicides / Q000494:pharmacology*; D011198:Solanum tuberosum / Q000201:enzymology; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013463:Sulfuric Acid Esters / Q000494:pharmacology*
D012556:Schistosomicides; D013439:Sulfhydryl Reagents; D013463:Sulfuric Acid Esters; D000251:Adenosine Triphosphatases; D001081:Apyrase; D005978:Glutathione; D004229:Dithiothreitol; D007460:Iodoacetamide