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Screening and Phenotypical Characterization of Schistosoma mansoni Histone Deacetylase 8 (SmHDAC8) Inhibitors as Multistage Antischistosomal Agents
journal contribution
posted on 2019-11-12, 14:35 authored by Fulvio Saccoccia, Margherita Brindisi, Roberto Gimmelli, Nicola Relitti, Alessandra Guidi, A Prasanth Saraswati, Caterina Cavella, Simone Brogi, Giulia Chemi, Stefania Butini, Giuliana Papoff, Johanna Senger, Daniel Herp, Manfred Jung, Giuseppe Campiani, Sandra Gemma, Giovina RubertiSchistosomiasis
(also known as bilharzia) is a neglected tropical
disease caused by platyhelminths of the genus Schistosoma. The disease is endemic in tropical and subtropical areas of the
world where water is infested by the intermediate parasite host, the
snail. More than 800 million people live in endemic areas and more
than 200 million are infected and require treatment. Praziquantel
(PZQ) is the drug of choice for schistosomiasis treatment and transmission
control being safe and very effective against adult worms of all the
clinically relevant Schistosoma species. Unfortunately,
it is ineffective on immature, juvenile worms; therefore, it does
not prevent reinfection. Moreover, the risk of development and spread
of drug resistance because of the widespread use of a single drug
in such a large population represents a serious threat. Therefore,
research aimed at identifying novel drugs to be used alone or in combination
with PZQ are needed. Schistosoma mansoni histone
deacetylase 8 (SmHDAC8) is a class I zinc-dependent
HDAC, which is abundantly expressed in all stages of its life cycle,
thus representing an interesting target for drug discovery. Through
virtual screening and phenotypical characterization of selected hits,
we discovered two main chemical classes of compounds characterized
by the presence of a hydroxamate-based metal binding group coupled
to a spiroindoline or a tricyclic thieno[3,2-b]indole
core as capping groups. Some of the compounds of both classes were
deeply investigated and showed to impair viability of larval, juvenile,
and adult schistosomes, to impact egg production in vitro and/or to induce morphological alterations of the adult schistosome
reproductive systems. Noteworthy, all of them inhibit the recombinant
form of SmHDAC8 enzyme in vitro.
Overall, we identified very interesting scaffolds, paving the way
to the development of effective antischistosomal agents.
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antischistosomal agentstransmission controlPZQdrug discoveryadult wormscompoundPhenotypical Characterizationadult schistosomeSchistosoma mansoni Histone Deacetylase 8zinc-dependent HDACSchistosoma mansoni histone deacetylase 8phenotypical characterizationlife cyclenovel drugsMultistage Antischistosomal Agents Schistosomiasischemical classesgenus Schistosomadrug resistanceSchistosoma speciesadult schistosomesparasite hostimpact egg productionschistosomiasis treatmentSm HDAC 8 enzymehydroxamate-based metal binding groupsubtropical areas
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