Target-Based Design of Praziquantel Analogs at Cestode TRPM<sub>PZQ</sub>
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 (TRPM<sub>PZQ</sub>), 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 TRPM<sub>PZQ</sub> binding pockets to design thioamide derivatives of PZQ with greater efficacy at pseudophyllidean cestode TRPM<sub>PZQ</sub>. Target-based design across parasite TRPM<sub>PZQ</sub> 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.
Authors
- Marc Kaethner (ORCID: https://orcid.org/0000-0001-8582-8517)
- Claudia M. Rohr (ORCID: https://orcid.org/0000-0003-0065-7160)
- Mina Ghobrial (ORCID: https://orcid.org/0000-0003-1449-3144)
- Daniel J. Sprague (ORCID: https://orcid.org/0000-0002-0709-3284)
- Jonathan S. Marchant (ORCID: https://orcid.org/0000-0001-6592-0877)
- Britta Lundström‐Stadelmann (ORCID: https://orcid.org/0000-0003-2672-5766)
- Thomas Spangenberg (ORCID: https://orcid.org/0000-0002-5654-8919)
- David Maillard (ORCID: https://orcid.org/0000-0002-8244-4515)
- Sang-Kyu Park (ORCID: https://orcid.org/0000-0002-3875-1227)
- D. Barth
Institutions
- University of Bern (CH)
- Medical University of South Carolina (US)
- Merck KGaA, Darmstadt (Germany) (DE)
- Medical College of Wisconsin (US)
- Office of Infectious Diseases (US)
- Institute of Chemical Engineering (BG)
- Institute of Cell Biology and Neurobiology (IT)
- Institut de Biologie Moléculaire et Cellulaire (FR)
- National Center for Infectious Diseases (US)
- Institute of Parasitology (CZ)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1021/acsinfecdis.5c00449
- Citations
- 2
- Primary Topic
- Parasite Biology and Host Interactions
- Type
- article
- Field-Weighted Citation Impact
- 3.43
Funders
- American Heart Association
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases