Faculty Collaboration Database

Metabolism of (R)-Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel. ChemMedChem 2023 Sep 15;18(18):e202300140

Date

06/05/2023

Pubmed ID

37272317

Pubmed Central ID

PMC10530395

DOI

10.1002/cmdc.202300140

Scopus ID

2-s2.0-85161895130 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPM_PZQ ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPM_PZQ , as well as serving as the primary site of oxidative metabolism which results in PZQ being a short-lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPM_PZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.

Author List

Friedrich L, Park SK, Ballard P, Ho Baeurle TH, Maillard D, Bödding M, Keiser J, Marchant JS, Spangenberg T

Authors

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Sang Kyu Park PhD Research Scientist I in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Anthelmintics
Humans
Parasites
Praziquantel
Schistosoma mansoni
TRPM Cation Channels
Transient Receptor Potential Channels