Screening and Phenotypical Characterization of Schistosoma mansoni Histone Deacetylase 8 (SmHDAC8) Inhibitors as Multistage Antischistosomal Agents

Abstract

Schistosomiasis (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[3,2b]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.

Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors

“…These differences should allow the development of inhibitors that are selective for the schistosome enzyme, thereby minimizing off‐target effects caused by interactions with the human (host) orthologues . A few smHDAC8 inhibitors have been described in the literature so far, such as J1038 and TH65 (Figure ) . These inhibitors are often aromatic hydroxamic acids and many exploit a hydrogen bond to the aforementioned histidine in the active site, whereas the methionine, which the human orthologue has in the same place, cannot be addressed in a similar fashion.…”

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

“…Taking these concerns into consideration and given the modern resources of drug development, synthesis of PZQ derivatives [8], discovery of alternative lead compounds [9,10], natural products [11,12] and repurposing of existing drugs [13,14] are effective approaches for the introduction of new antischistosomal agents. Recently, we demonstrated that miltefosine (MFS), a membrane active alkylphosphocholine, is a promising repurposing candidate against schistosomiasis [13,15].…”

The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

“…These compounds have shown some selective activity on SmHDAC8 over the major H. sapiens HDAC isoforms (HDAC1 and HDAC6), although the activities against SmHDAC8 and the human HDAC8 were similar [30]. HDACs inhibitors showing a preference for one isoform have been proposed as therapeutic compounds in cancer and other diseases, including parasitic diseases [30,[43][44][45][46]. This is because isoform-selective inhibitors can alter distinct pathways more specifically involved in disease mechanisms, contrary to broad-spectrum HDAC inhibitors, which can alter multiple cellular processes, thus causing higher toxic effects [43].…”