2. Academic Validation
  3. Benzodeazaoxaflavin Sirtuin Inhibitors Inhibit Schistosoma mansoni Sirt2 and Cause Phenotypic Changes and Lethality in Schistosomula and Adult Worm Stages

Benzodeazaoxaflavin Sirtuin Inhibitors Inhibit Schistosoma mansoni Sirt2 and Cause Phenotypic Changes and Lethality in Schistosomula and Adult Worm Stages

  • ACS Infect Dis. 2025 Nov 14;11(11):3115-3127. doi: 10.1021/acsinfecdis.5c00515.
Roberto Gimmelli 1,  Giuliana Papoff 1,  Emanuele Fabbrizi 2,  Michela Guida 2,  Cristiana Lalli 1,  Fulvio Saccoccia 1,  Cécile Häberli 3 4,  Jennifer Keiser 3 4,  Daria Monaldi 5,  Manfred Jung 5,  Christophe Romier 6,  Dante Rotili 7 8,  Antonello Mai 2,  Giovina Ruberti 1
Affiliations

Affiliations

  • 1 Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Adriano Buzzati-Traverso Campus, Monterotondo, Rome 00015, Italy.
  • 2 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome 00185, Italy.
  • 3 Swiss Tropical and Public Health Institute, Allschwil 4002, Switzerland.
  • 4 University of Basel, Basel 4001, Switzerland.
  • 5 Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg 79104, Germany.
  • 6 Département de Biologie Structurale Intégrative, Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch Cedex 67404, France.
  • 7 Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.
  • 8 Biostructures and Biosystems National Institute (INBB), Via dei Carpegna 19, Rome 00165, Italy.
PMID: 41056475 DOI: 10.1021/acsinfecdis.5c00515
Abstract

Schistosomiasis, a neglected tropical disease caused by trematodes of Schistosoma genus, urgently requires new treatments due to praziquantel's limited efficacy against juvenile worms as well as the threat of drug resistance. In this study, we evaluated a series of benzodeazaoxaflavin (BDF4)-based compounds as inhibitors of the parasite's epigenetic enzyme SmSIRT2. Three compounds, 7-9 (MC2346, MC2141, and MC2345), showed activity against both Liberian and Puerto Rican strains of Schistosoma mansoni. The compounds reduced schistosomula and adult worm pair viability, pairing, and egg production, with low cytotoxicity in mammalian cells. These effects were linked to histone H3 hyperacetylation and cytochrome c-mediated Apoptosis, confirming SmSIRT2 as a functional target. These findings support the development of SmSIRT2 inhibitors as novel antischistosomal agents with therapeutic potential for both curative and preventive applications. Further in vivo studies are warranted to assess their pharmacokinetic and safety profiles.

Keywords

Schistosoma mansoni; SmSirt2 inhibitors; phenotypic and biochemical characterization; sirtuins.

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