Fluorobenzoyl dipeptidyl derivatives as inhibitors of the <i>Fasciola hepatica</i> cysteine protease cathepsin L1

Moran, Brian W.; Anderson, Frankie P.; Ruth, Deborah M.; Fágáin, Ciarán Ó; Dalton, John P.; Kenny, Peter T.M.

doi:10.3109/14756360902888184

Cited by 7 publications

(1 citation statement)

References 19 publications

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“…Due to their role in human disease and tumour progression, inhibitors targeting cysteine proteases have been extensively studied. Most efforts were focused on peptidic inhibitors with different substituents such as aminoacetonitriles, heterocyclic ketones, nitriles, epoxides and vinyl sulfones [ 19 , 20 , 21 ]. Many of these small molecules contain electrophilic groups that bind in the active-site through covalent interactions with the catalytic cysteine either in a reversible or irreversible way.…”

Section: Introductionmentioning

confidence: 99%

Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach

Ferraro¹,

Merlino²,

́Oca³

et al. 2016

PLoS Negl Trop Dis

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BackgroundIncreased reports of human infections have led fasciolosis, a widespread disease of cattle and sheep caused by the liver flukes Fasciola hepatica and Fasciola gigantica, to be considered an emerging zoonotic disease. Chemotherapy is the main control measure available, and triclabendazole is the preferred drug since is effective against both juvenile and mature parasites. However, resistance to triclabendazole has been reported in several countries urging the search of new chemical entities and target molecules to control fluke infections.Methodology/Principle FindingsWe searched a library of forty flavonoid derivatives for inhibitors of key stage specific Fasciola hepatica cysteine proteases (FhCL3 and FhCL1). Chalcones substituted with phenyl and naphtyl groups emerged as good cathepsin L inhibitors, interacting more frequently with two putative binding sites within the active site cleft of the enzymes. One of the compounds, C34, tightly bounds to juvenile specific FhCL3 with an IC50 of 5.6 μM. We demonstrated that C34 is a slow-reversible inhibitor that interacts with the Cys-His catalytic dyad and key S2 and S3 pocket residues, determinants of the substrate specificity of this family of cysteine proteases. Interestingly, C34 induces a reduction in NEJ ability to migrate through the gut wall and a loss of motility phenotype that leads to NEJ death within a week in vitro, while it is not cytotoxic to bovine cells.Conclusions/SignificanceUp to date there are no reports of in vitro screening for non-peptidic inhibitors of Fasciola hepatica cathepsins, while in general these are considered as the best strategy for in vivo inhibition. We have identified chalcones as novel inhibitors of the two main Cathepsins secreted by juvenile and adult liver flukes. Interestingly, one compound (C34) is highly active towards the juvenile enzyme reducing larval ability to penetrate the gut wall and decreasing NEJ´s viability in vitro. These findings open new avenues for the development of novel agents to control fluke infection and possibly other helminthic diseases.

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Section: Introductionmentioning

confidence: 99%

Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach

Ferraro¹,

Merlino²,

́Oca³

et al. 2016

PLoS Negl Trop Dis

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Novel palladium(II) complexes containing a sulfur ligand: structure and biological activity on HeLa cells

et al. 2011

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Two novel palladium(II) complexes with a thiosalicylic acid (HSC(6)H(4)CO(2)H) ligand, with the formulas [Pd(TSA)(L)]·mH(2)O (TSA is thiosalicylic acid; in complex 1, L is 1,10-phenanthroline and m = 1; in complex 2, L is 2,2'-bipyridine and m = 2), have been synthesized and characterized. The coordination geometry of both palladium atoms is square planar; they are four-coordinated and each is coordinated in an N,N,O(-),S(-) mode. There is a sigmoid oxygen chain in complex 1, but an oxygen ring in complex 2. The competitive binding of the complexes to HeLa cell DNA (HL-DNA) has been investigated by fluorescence spectroscopy. The results show that the two complexes have the ability to bind with HL-DNA. Viscosity studies suggest that the complexes bind to DNA by intercalation. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the HL-DNA. The two complexes exhibit cytotoxic specificity and a significant cancer cell inhibitory rate. The apoptosis tests indicated that the complexes have an apoptotic effect. Furthermore, complex 1 exhibits more biological activity than complex 2, which is mainly because the area of the aromatic ring of 1,10-phenanthroline is larger than that of 2,2'-bipyridine.

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An update on proteases and protease inhibitors from trematodes

Horn,

Bieliková,

Vostoupalová

et al. 2024

Advances in Parasitology

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Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1

Cited by 7 publications

References 19 publications

Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach

Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach

Novel palladium(II) complexes containing a sulfur ligand: structure and biological activity on HeLa cells

An update on proteases and protease inhibitors from trematodes

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