Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 298, Issue 10, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2022.102375
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Funding
- Ministero dell Universite della Ricerca (MUR) [20154JRJPP]
- CNR (National Research Council) - CNCCS (Collezione Nazionale di Composti Chimici e Centro di Screening) Rare, Neglected and Poverty Related Diseases Schisto-discovery Project [DSB.AD011.001.003]
- Lazio Innova POR FESR Lazio 2014 to 2020 HDACiPLAT Project [A0375-2020-36575]
- MUR-PRIN grant
- CNR-CNCCS grant
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Parasitic diseases, such as schistosomiasis, pose a significant global health burden, particularly in impoverished regions. A study has identified two novel schistosomicidal spiroindoline derivatives that can selectively inhibit the activity of the schistosome enzyme HDAC8, paving the way for the development of improved HDAC8-selective allosteric inhibitors. This finding is important for the development of new treatments for parasitic diseases.
Parasitic diseases cause significant global morbidity and mortality particularly in the poorest regions of the world. Schistosomiasis, one of the most widespread neglected tropical diseases, affects more than 200 million people worldwide. Histone deacetylase (HDAC) inhibitors are prominent epigenetic drugs that are being investigated in the treatment of several diseases, including cancers and parasitic diseases. Schistosoma mansoni HDAC8 (SmHDAC8) is highly expressed in all life cycle stages of the parasite, and selective inhibition is required in order to avoid undesirable off-target effects in the host. Herein, by X-ray crystal structures of SmHDAC8inhibitor complexes, biochemical and phenotypic studies, we found two schistosomicidal spiroindoline derivatives binding a novel site, next to Trp198, on the enzyme surface. We determined that by acting on this site, either by mutation of the Trp198 or by compound binding, a decrease in the activity of the enzyme is achieved. Remarkably, this allosteric site differs from the human counterpart; rather, it is conserved in all Schistosoma species, as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.
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