Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis
Open accessAbstract
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
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Many of the 3-benzamido-benzohydroxamate inhibitors subsequently developed displayed higher potency than 1 in inhibiting smHDAC8.
“Many of the 3-benzamido-benzohydroxamate inhibitors that were subsequently developed displayed higher potency than 1 in inhibiting smHDAC8 29”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [29]
Inhibitor 1 exploits smHDAC8-specific interactions with residues K20 and H292.
“This inhibitor also exploits smHDAC8-specific interactions with residues K20 and H292 (hHDAC8 K33 and M274) 29”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [29]
Previous work has yielded a series of 3-benzamido-benzohydroxamates that show strong selectivity for smHDAC8 and hHDAC8 over other human HDACs.
“Previous work on the selective inhibition of smHDAC8 has yielded the development of an inhibitor series of 3-benzamido-benzohydroxamates that show strong selectivity for smHDAC8 and hHDAC8 over other human HDACs 29”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [29]
smHDAC8 crystals can be used to look at inhibitor binding in a crystal lattice-unbiased manner.
“We have previously shown that our smHDAC8 crystals can be used to look at inhibitor binding in a crystal latticeunbiased manner 29, 30, 55-58 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [29]
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HDAC8: a multifaceted target for therapeutic interventions
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Marek, M., Shaik, T. B., Heimburg, T., Chakrabarti, A., Lancelot, J., Ramos-Morales, E., Da Veiga, C., Kalinin, D., Melesina, J., Robaa, D., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01087 · Cited by 123 · see citing works
Self-citationStrategies To Design Selective Histone Deacetylase Inhibitors
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Self-citationTargeting Histone Deacetylase 8 as a Therapeutic Approach to Cancer and Neurodegenerative Diseases
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- Authors
- Heimburg, T., Chakrabarti, A., Lancelot, J., Marek, M., Melesina, J., Hauser, A.-T., Shaik, T. B., Duclaud, S., Robaa, D., Erdmann, F., Schmidt, M., Romier, C., Pierce, R. J., Jung, M., & Sippl, W.
- Affiliations
- Martin Luther University Halle-Wittenberg (DE)
- University of Freiburg (DE)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-03-03
- Volume
- 59
- Issue
- 6
- Pages
- 2423-2435
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2291959355
- Cited by
- 124
- References
- 6
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 9 · 2023: 10 · 2022: 13 · 2021: 11 · 2020: 12 · 2019: 21 · 2018: 16 · 2017: 16 · 2016: 7
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (Ju295/13-1, Si868/13-1)
- Agence Nationale de la Recherche (ANR-10-INSB-05-01)
- Institut national de la santé et de la recherche médicale (NA)
- Centre National de la Recherche Scientifique (NA)
- Seventh Framework Programme (241865, 602080)
- Institut Pasteur de Lille (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- Schistosoma mansoni, schistosomiasis, HDAC8 inhibitors, histone deacetylase, structure-based drug design, enzyme inhibition, drug selectivity, oviposition, praziquantel alternatives, neglected parasitic diseases
- MeSH terms
- Animals, Dose-Response Relationship, Drug, Histone Deacetylases, Humans, Larva, Models, Molecular, Schistosoma mansoni, Schistosomiasis mansoni, Schistosomicides, Structure-Activity Relationship, Substrate Specificity, X-Ray Diffraction, Helminth Proteins, Drug Delivery Systems
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