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

Saccoccia, Fulvio; Pozzetti, Luca; Gimmelli, Roberto; Butini, Stefania; Гуиди, Алессандра; Papoff, Giuliana; Giannaccari, Marialaura; Brogi, Simone; Scognamiglio, Viviana; Gemma, Sandra; Ruberti, Giovina; Campiani, Giuseppe

doi:10.1016/j.jbc.2022.102375

Cited by 4 publications

(12 citation statements)

References 57 publications

(126 reference statements)

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“…Interestingly, these compounds were proved to inhibit the enzyme in a mixed/allosteric manner. 43,53 From the screening of a small series of structurally diverse HDAC inhibitors against a panel of different parasites, including S. mansoni, inhibitor 18 (Figure 4) was identified as the most potent against all of the considered parasites. The high toxicity exerted by this derivative against host cells led to testing of some structurally related analogs, characterized by the presence of a tert-butyl carbamate substituent, as a key common feature, at the meta or para position of the (3acryloyl)phenyl moiety and of the hydroxamate function as the ZBG.…”

Section: Histone Deacetylasesmentioning

confidence: 99%

“…In a follow-up study, X-ray cocrystal structures clarified the binding mode of complexed structures, allowing the discovery of two spiroindoline derivatives, 17a , b , binding a specific site different from the catalytic site, in the vicinity of Trp198 on the enzyme surface. Interestingly, these compounds were proved to inhibit the enzyme in a mixed/allosteric manner. , …”

Section: Histone Deacetylasesmentioning

confidence: 99%

“…95,96 A catechol moiety also characterizes a set of cinnamides, previously synthesized to target human arginase, that displayed interesting activity against LaARG. The compound caffeic acid phenethyl amide (53), which resulted in a weak inhibitor of human arginase (IC 50 = 60.3 μM), was found to be 9-fold more potent against the parasite enzyme (IC 50 = 6.9 μM). Subsequently, other compounds, including those that did not inhibit human arginase, were tested against LaARG, showing IC 50 values between 1.3 and 17.8 μM.…”

Section: Arginase Inhibitors In Leishmaniasismentioning

confidence: 99%

See 2 more Smart Citations

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Rossi,

Tudino,

Carullo

et al. 2024

ACS Infect. Dis.

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The term "zoonosis" denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low-and middleincome nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.

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Section: Histone Deacetylasesmentioning

confidence: 99%

Section: Histone Deacetylasesmentioning

confidence: 99%

Section: Arginase Inhibitors In Leishmaniasismentioning

confidence: 99%

See 1 more Smart Citation

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Rossi,

Tudino,

Carullo

et al. 2024

ACS Infect. Dis.

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“…Unfortunately, there is currently no vaccine available for human use against S. mansoni [ 5 ]. The sole treatment option is praziquantel (PZQ) monotherapy, which is vulnerable to drug resistance and has limited effectiveness against the juvenile stage [ 6 , 7 ]. Therefore, there is a pressing need for alternative treatment approaches [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…The histone deacetylase (HDAC) enzymes are attractive targets for developing therapeutics against Schistosoma [ 7 ]. HDACs are lysine deacetylases that rely on NAD + or Zn 2+ and regulate transcription, chromatin structure, gene expression, and several cytoplasmic signaling pathways [ 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation

et al. 2023

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Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma, with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it is vulnerable to drug resistance and ineffective in the juvenile stage. Therefore, identifying new treatments is crucial. SmHDAC8 is a promising therapeutic target, and a new allosteric site was discovered, providing the opportunity for the identification of a new class of inhibitors. In this study, molecular docking was used to screen 13,257 phytochemicals from 80 Saudi medicinal plants for inhibitory activity on the SmHDAC8 allosteric site. Nine compounds with better docking scores than the reference were identified, and four of them (LTS0233470, LTS0020703, LTS0033093, and LTS0028823) exhibited promising results in ADMET analysis and molecular dynamics simulation. These compounds should be further explored experimentally as potential allosteric inhibitors of SmHDAC8.

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Effects of structurally distinct human HDAC6 and HDAC6/HDAC8 inhibitors against S. mansoni larval and adult worm stages

Gimmelli,

Papoff,

Saccoccia

et al. 2024

PLoS Negl Trop Dis

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Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide caused by Platyhelminthes of the genus Schistosoma. The treatment of schistosomiasis relies on the long-term application of a single safe drug, praziquantel (PZQ). Unfortunately, PZQ is very effective on adult parasites and poorly on larval stage and immature juvenile worms; this can partially explain the re-infection in endemic areas where patients are likely to host parasites at different developmental stages concurrently. Moreover, the risk of development of drug resistance because of the widespread use of a single drug in a large population is nowadays a serious threat. Hence, research aimed at identifying novel drugs to be used alone or in combination with PZQ is needed. Schistosomes display morphologically distinct stages during their life cycle and epigenetic mechanisms are known to play important roles in parasite growth, survival, and development. Histone deacetylase (HDAC) enzymes, particularly HDAC8, are considered valuable for therapeutic intervention for the treatment of schistosomiasis. Herein, we report the phenotypic screening on both larvae and adult Schistosoma mansoni stages of structurally different HDAC inhibitors selected from the in-house Siena library. All molecules have previously shown inhibition profiles on human HDAC6 and/or HDAC8 enzymes. Among them we identified a quinolone-based HDAC inhibitor, NF2839, that impacts larval and adult parasites as well as egg viability and maturation in vitro. Importantly, this quinolone-based compound also increases histone and tubulin acetylation in S. mansoni parasites, thus representing a leading candidate for the development of new generation anti-Schistosoma chemotherapeutics.

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

Cited by 4 publications

References 57 publications

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation

Effects of structurally distinct human HDAC6 and HDAC6/HDAC8 inhibitors against S. mansoni larval and adult worm stages

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