The identification of inhibitors of Schistosoma mansoni miracidial transformation by incorporating a medium-throughput small-molecule screen.
In Schistosoma mansoni, the miracidium-to-primary sporocyst transformation process is associated with many physiological, morphological, transcriptional and biochemical changes. In the present study, we use a medium-throughput small-molecule screen to identify chemical compounds inhibiting or delaying the in vitro transformation of miracidia to the sporocyst stage. The Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) contains 1280 well-characterized chemical compounds with various modes of action including enzyme inhibitors, antibiotics, cell-cycle regulators, apoptosis inducers and GPCR ligands. We identified 47 compounds that greatly reduce or delay this transformation process during a primary screen of live miracidia. The majority of compounds inhibiting larval transformation were from dopaminergic, serotonergic, ion channel and phosphorylation classes. Specifically, we found that dopamine D2-type antagonists, serotonin reuptake inhibitors, voltage-gated calcium channel antagonists and a PKC activator significantly reduced in vitro miracidial transformation rates. Many of the targets of these compounds regulate adenylyl cyclase activity, with the inhibition or activation of these targets resulting in increased cAMP levels in miracidia and concomitant blocking/delaying of larval transformation.
Taft
Andrew S
AS
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA. tafta@svm.vetmed.wisc.edu
Norante
Francesca A
FA
Yoshino
Timothy P
TP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D002997:Clomipramine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007150:Immunohistochemistry; D051379:Mice; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000254:growth & development; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014273:Triflupromazine / Q000494:pharmacology
D000871:Anthelmintics; D053119:Benzophenanthridines; D002121:Calcium Channel Blockers; D015283:Citalopram; D005576:Colforsin; D000001:Calcimycin; D000242:Cyclic AMP; C016299:chelerythrine; D013755:Tetradecanoylphorbol Acetate; D002997:Clomipramine; D014273:Triflupromazine; D015056:1-Methyl-3-isobutylxanthine; D004121:Dimethyl Sulfoxide