Identification and characterisation of the tegument-expressed aldehyde dehydrogenase SmALDH_312 of Schistosoma mansoni, a target of disulfiram

Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ) is the only drug for schistosomiasis, alternatives are needed. By a biochemical approach, we identified a tegumentally expressed a...

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Veröffentlicht in:European journal of medicinal chemistry 2023-05, Vol.251, p.115179-115179, Article 115179
Hauptverfasser: Beutler, Mandy, Harnischfeger, Julie, Weber, Michael H.W., Hahnel, Steffen R., Quack, Thomas, Blohm, Ariane, Ueberall, Monique E., Timm, Thomas, Lochnit, Günter, Rennar, Georg A., Gallinger, Tom L., Houhou, Hicham, Rahlfs, Stefan, Falcone, Franco H., Becker, Katja, Schlitzer, Martin, Haeberlein, Simone, Czermak, Peter, Salzig, Denise, Grevelding, Christoph G.
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Sprache:eng
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Zusammenfassung:Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ) is the only drug for schistosomiasis, alternatives are needed. By a biochemical approach, we identified a tegumentally expressed aldehyde dehydrogenase (ALDH) of S. mansoni, SmALDH_312. Molecular analyses of adult parasites showed Smaldh_312 transcripts in both genders and different tissues. Physiological and cell-biological experiments exhibited detrimental effects of the drug disulfiram (DSF), a known ALDH inhibitor, on larval and adult schistosomes in vitro. DSF also reduced stem-cell proliferation and caused severe tegument damage in treated worms. In silico-modelling of SmALDH_312 and docking analyses predicted DSF binding, which we finally confirmed by enzyme assays with recombinant SmALDH_312. Furthermore, we identified compounds of the Medicine for Malaria Venture (MMV) pathogen box inhibiting SmALDH_312 activity. Our findings represent a promising starting point for further development towards new drugs for schistosomiasis. [Display omitted] •A tegumentally expressed aldehyde dehydrogenase, SmALDH_312, was discovered in the human parasite Schistosoma mansoni.•SmALDH_312 is expressed in adult and larval stages of the parasite.•The ALDH inhibitor disulfiram caused severe effects in adult and larval schistosomes in vitro.•In silico-modelling, docking analyses, and enzyme assays demonstrated SmALDH_312 binding and inhibition by disulfiram.•SmALDH_312-inhibiting compounds of the Medicine for Malaria Venture box with anti-schistosomal activity were identified.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2023.115179