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A fission yeast-based platform for nematode PDE inhibitor discovery
Sarah Bibeau1, Natalie Chen1, Hannah Sutoris1
1Biology Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467, USA.
Cellular Signalling
|March 28, 2026
Summary
Researchers screened small molecules against C. elegans cyclic nucleotide phosphodiesterases (PDEs). A key amino acid difference explains resistance to inhibitors, offering a strategy for developing new anthelmintic and nematicidal drugs targeting parasitic nematodes.
Area of Science:
- Biochemistry
- Molecular Biology
- Parasitology
Background:
- Class I cyclic nucleotide phosphodiesterases (PDEs) are crucial enzymes regulating cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling.
- Mammalian PDEs are druggable targets, with potent inhibitors developed.
- Nematode genomes, including Caenorhabditis elegans and parasitic species, contain six PDE genes.
Purpose of the Study:
- To screen for small molecule inhibitors targeting C. elegans PDEs.
- To investigate the structural basis for differential inhibitor sensitivity between mammalian and nematode PDEs.
- To explore the potential of identified inhibitors as anthelmintic and nematicidal agents.
Main Methods:
- Expression of C. elegans PDEs in Schizosaccharomyces pombe.
- High-throughput screening of mammalian PDE inhibitors against C. elegans PDEs.
- Site-directed mutagenesis to investigate amino acid differences impacting inhibitor sensitivity.
- Assessment of C. elegans growth and fertility upon exposure to active inhibitors.
Main Results:
- Several small molecule inhibitors showed activity against C. elegans PDEs.
- C. elegans PDE-4 exhibits insensitivity to mammalian PDE4 inhibitors like Rolipram, attributed to a single amino acid difference (R580T).
- Specific inhibitors demonstrated toxicity and reduced fecundity in C. elegans.
Conclusions:
- The study identifies druggable C. elegans PDEs and provides insights into inhibitor resistance mechanisms.
- A strategy for discovering novel anthelmintic and nematicidal compounds targeting parasitic nematode PDEs is presented.
- The findings support the development of new therapies against nematode infections.
