Histone Deacetylase (HDAC) Inhibitors for the Treatment of Schistosomiasis

Abstract

Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. Schistosomes display morphologically distinct stages during their life cycle and the transformations between stages are controlled by epigenetic mechanisms. The targeting of epigenetic actors might therefore represent the parasites’ Achilles’ heel. Specifically, histone deacetylases have been recently characterized as drug targets for the treatment of schistosomiasis. This review focuses on the recent development of inhibitors for schistosome histone deacetylases. In particular, advances in the development of inhibitors of Schistosoma mansoni histone deacetylase 8 have indicated that targeting this enzyme is a promising approach for the treatment of this infection.

Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors

“…Sm HDAC8 emerged as a good target for the development of new synthetic compounds with schistosomicidal activity ( 23 , 24 ). Several compounds have been shown to inhibit the enzymatic activity of recombinant Sm HDAC8 in the nanomolar to mid-micromolar range by binding the active site ( 10 , 11 , 15 , 16 , 17 , 18 , 19 , 20 ). So far, the identified compounds are likely acting as competitive inhibitors, although in the majority of studies, the actual nature of the enzyme inhibition was not deeply investigated.…”

“…SmHDAC8 is a metal-dependent enzyme, harboring a zinc ion in the active site, and, so far, the vast majority of discovered inhibitors own a zinc-binding group, a hydroxamate or a sulfur moiety (10), Specificity toward different HDAC isoforms may be obtained by an appropriately designed linker and cap groups or by exploiting specific and unique regulatory sites. Through a concerted effort involving molecular modeling, phenotypic screening, and enzymatic inhibition assays of SmHDAC8 enzyme, we previously identified novel HDAC inhibitors as promising multi-stage antischistosomicidal hits (11).…”

“…Sm HDAC8 is a metal-dependent enzyme, harboring a zinc ion in the active site, and, so far, the vast majority of discovered inhibitors present a zinc-binding group, such as a hydroxamate or a sulfur moiety ( 10 ). Specificity toward different HDAC isoforms may be obtained by an appropriately designed linker and cap groups or by exploiting specific and unique regulatory sites.…”

Virtual Screening in the Identification of Sirtuins’ Activity Modulators

“…In addition to human isoforms, parasitic sirtuins represent an important target to treat various protozoa-related diseases [ 315 , 316 , 317 , 318 , 319 , 320 ]. This is due to the importance of sirtuins in different physiological processes of the parasite [ 321 ], but an important warning is represented by selectivity issues toward the host’s isoforms.…”

In vitro evaluation of Resveratrol as a potential pre-exposure prophylactic drug against Trypanosoma cruzi infection

“…Coding sequences for several of these enzymes have been found in the T. cruzi genome ( El-Sayed et al., 2005 ), and partially characterized ( Moretti et al., 2015 ; Ritagliati et al., 2015 ; Marek et al., 2021 ; Picchi-Constante et al., 2021 ). Inhibitors of KDACs have been found to affect different parasites, including the pathogen causing malaria ( Plasmodium falciparum ), kinetoplastids ( T. cruzi , Trypanosoma brucei and Leishmania donovani ), and nematodes ( Brugiamalayi, Dirofilariaimmitis and Haemonchus contortus ) ( Murray et al., 2001 ; Andrews et al., 2012a , 2012b ; Herrera-Martínez et al., 2020 ; Ghazy et al., 2022 ; Ângelo de Souza et al., 2020 ; Veiga-santos et al., 2014 ; Verçoza et al., 2017 ; de Oliveira Santos et al., 2019 ; Matutino Bastos et al., 2020 ). Moreover, we have recently reported that resveratrol (RSV), previously described as an activator of sirtuin deacetylases ( Andrews et al., 2012b ; Dai et al., 2018 ), reduces the growth of T. cruzi epimastigotes and the infectivity of cell-derived trypomastigotes ( Campo, 2017 ), which agrees with previous reports describing the anti-parasite effects of RSV on Leishmania major ( Kedzierski et al., 2007 ) and other T. cruzi strains ( Valera Vera et al., 2016 ).…”