Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro
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Schistosomes and other parasitic platyhelminths cause infectious diseases of worldwide significance for humans and animals. Despite their medical and economic importance, vaccines are not available and the number of drugs is alarmingly limited. For most platyhelminths including schistosomes, Praziquantel (PZQ) is the commonly used drug. With respect to its regular application in mass treatment programs, however, there is increasing concern about resistance development.
Previous studies demonstrated that inhibitors used to treat non-parasitic human diseases may be useful to be tested for their effects on parasites. To this end, we focused on biarylalkyl carboxylic acids (BACAs) as basis, which had been shown before to be interesting candidates in the context of finding alternative approaches to treat diabetes mellitus. We tested 32 chemically modified derivatives of these substances (biarylalkyl carboxylic acid derivatives (BACADs)) for their effects on adult Schistosoma mansoni in vitro. Treatment with 18 BACADs resulted in egg production-associated phenotypes and reduced pairing stability. In addition, 12 of these derivatives affected vitality and/or caused severe tegument damage, gut dilatation, or other forms of tissue disintegration which led to the death of worms. In most cases (10/12), one derivative caused more than one phenotype at a time. In vitro experiments in the presence of serum albumin (SA) and alpha-acidic glycoprotein (AGP) indicated a varying influence of these blood components on the effects of two selected derivatives. The variety of observed phenotypes suggested that different targets were hit. The results demonstrated that BACADs are interesting substances with respect to their anti-schistosomal effects.
KeywordsSchistosoma mansoni Platyhelminths Biarylalkyl carboxylic acid In vitro culture Drug development Serum component
The authors thank Christina Scheld and Mathias Riedl for excellent technical assistance and Simone Häberlein for critically reading the manuscript. This work was supported by the Wellcome Trust, grant number 107475/Z/15/Z (FUGI). Ariane Blohm (AB) was financially supported by the following foundations: “Stiftung der Eheleute Dr. med. vet. Hans-Joachim und Gertrud Engemann” and “Karl-Enigk-Stiftung.” Furthermore, AB was a member of the International Giessen Graduate Centre for The Life Sciences (GGL; Germany).
Compliance with ethical standards
All animal experiments were performed in accordance with the European regulations (ETS 123; revised Appendix A) and were approved by the Regional Council, Giessen, Germany (V54-19 c 20/15 c GI 18/10 and V54-19 c 20/15 (1) GI 18/10 - Nr. 75/2009). Thus, all procedures performed in this study involving animals were in accordance with the ethical standards of the institution or practice at which this study was conducted.
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