Effects of structurally distinct human HDAC6 and HDAC6/HDAC8 inhibitors against S. mansoni larval and adult worm stages.

Autor: Gimmelli R; Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Adriano Buzzati-Traverso Campus, Monterotondo, Rome, Italy.; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Roma, Italy., Papoff G; Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Adriano Buzzati-Traverso Campus, Monterotondo, Rome, Italy., Saccoccia F; Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Adriano Buzzati-Traverso Campus, Monterotondo, Rome, Italy., Lalli C; Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Adriano Buzzati-Traverso Campus, Monterotondo, Rome, Italy., Gemma S; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy., Campiani G; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy., Ruberti G; Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Adriano Buzzati-Traverso Campus, Monterotondo, Rome, Italy.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2024 Feb 28; Vol. 18 (2), pp. e0011992. Date of Electronic Publication: 2024 Feb 28 (Print Publication: 2024).
DOI: 10.1371/journal.pntd.0011992
Abstrakt: Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide caused by Platyhelminthes of the genus Schistosoma. The treatment of schistosomiasis relies on the long-term application of a single safe drug, praziquantel (PZQ). Unfortunately, PZQ is very effective on adult parasites and poorly on larval stage and immature juvenile worms; this can partially explain the re-infection in endemic areas where patients are likely to host parasites at different developmental stages concurrently. Moreover, the risk of development of drug resistance because of the widespread use of a single drug in a large population is nowadays a serious threat. Hence, research aimed at identifying novel drugs to be used alone or in combination with PZQ is needed. Schistosomes display morphologically distinct stages during their life cycle and epigenetic mechanisms are known to play important roles in parasite growth, survival, and development. Histone deacetylase (HDAC) enzymes, particularly HDAC8, are considered valuable for therapeutic intervention for the treatment of schistosomiasis. Herein, we report the phenotypic screening on both larvae and adult Schistosoma mansoni stages of structurally different HDAC inhibitors selected from the in-house Siena library. All molecules have previously shown inhibition profiles on human HDAC6 and/or HDAC8 enzymes. Among them we identified a quinolone-based HDAC inhibitor, NF2839, that impacts larval and adult parasites as well as egg viability and maturation in vitro. Importantly, this quinolone-based compound also increases histone and tubulin acetylation in S. mansoni parasites, thus representing a leading candidate for the development of new generation anti-Schistosoma chemotherapeutics.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Gimmelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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