2. Academic Validation
  3. Target-Based Design of Praziquantel Analogs at Cestode TRPMPZQ

Target-Based Design of Praziquantel Analogs at Cestode TRPMPZQ

  • ACS Infect Dis. 2025 Aug 3. doi: 10.1021/acsinfecdis.5c00449.
Daniel J Sprague 1 2 3,  Sang-Kyu Park 1,  Marc Kaethner 4 5,  Claudia M Rohr 1,  Mina R Ghobrial 1,  D Connor Barth 3,  David Maillard 6,  Thomas Spangenberg 7,  Britta Lundström-Stadelmann 4 8,  Jonathan S Marchant 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • 2 Program in Chemical Biology, Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • 3 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
  • 4 Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Berne, Switzerland.
  • 5 Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Berne, Switzerland.
  • 6 Central Process Development - Downstream Processing Services, Merck Electronics KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
  • 7 Global Health R&D of the Healthcare Business of Merck KGaA, Darmstadt, Germany, Ares Trading S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), 1262 Eysins, Switzerland.
  • 8 Multidisciplinary Center for Infectious Diseases, University of Bern, 3012 Berne, Switzerland.
PMID: 40754814 DOI: 10.1021/acsinfecdis.5c00449
Abstract

The drug praziquantel (PZQ) has been used for decades to treat clinical and veterinary infections caused by parasitic flatworms. Although PZQ is efficacious against many different types of flukes and tapeworms, PZQ activity is lower against certain types of parasites, including pseudophyllidean cestodes. The target of PZQ is a parasitic flatworm transient receptor potential ion channel (TRPMPZQ), and interrogation of this target affords the opportunity to understand why PZQ efficacy varies between different parasites and how target-based design strategies could help deliver new analogs with improved efficacy against currently hard-to-treat diseases. In this study, we consider natural amino acid variation within cestode TRPMPZQ binding pockets to design thioamide derivatives of PZQ with greater efficacy at pseudophyllidean cestode TRPMPZQ. Target-based design across Parasite TRPMPZQ orthologues, as well as at Other TRPM paralogues in this ion channel family, provides an opportunity to expand and improve on the current anthelmintic toolbox.

Keywords

TRP channel; ion channel; parasite; tapeworm.

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