Short communication20S proteasome as novel biological target for organochalcogenanes
Graphical abstract
Introduction
Biological investigations on selenium- and tellurium-containing compounds have increased in last decade. These compounds were thought to be deleterious but, recent studies have been proven otherwise and beneficial pleiotropic activities have been described. Antioxidative (as GPx mimetics) [1], anti-inflammatory [2], [3], neuroprotective [4], cancer prevention [5], pro-apoptotic [6] and immunomodulatory activities [7] are some of the biological properties described for selenium and tellurium-containing compounds. And that includes structure-based design of small molecules as enzyme inhibitors such as calpains, papain, cathepsins, protein tyrosine phosphatases [8]. The biological response for selenium- and tellurium-containing compounds commonly relies on an interaction with some sulfhydryl enzymes [9]. Pioneering demonstrated that inorganic telluranes are able to inhibit thiol-dependent enzymes but are inactive against oxygen-nucleophilic (O-nucleophilic) proteases (e.g. serine proteases) [10]. After that, the potential of chalcogenanes (organic and inorganic) has focused on thiol-dependent enzymes. Even when it was demonstrated that organotelluranes are more reactive species (more powerful inhibitors of thiol-dependent proteases) [11] than inorganic ones the possible activity of organotelluranes (and organoselenuranes) against other proteases was not explored. In this way, we decided to explore these possibilities, by demonstrating that organoselenuranes are capable of inhibiting cysteine cathepsins, a thiol-dependent proteases family [12] and we also established the structure–activity relationships involving both organoselenuranes and organotelluranes and cysteine cathepsins V and S [13]. Based on ours previous reports, we have considered the possibility that chalcogenated organic compounds can inhibit another class of protease, since, as aforementioned, only inorganic telluranes were evaluated against serine proteases [10]. To the best of our knowledge, interactions of selenium- and tellurium-containing organic compounds with non-thiol-dependent proteases are yet unknown. For that, we chosen as target the proteasome, a threonine protease (O-nucleophilic protease) which is responsible for all non-lysosomal cellular proteolysis in cell [14]. This enzyme is a multi-catalytic protease with a proteolytic core (20S proteasome, 20S PT), which contains three catalytic sites (β1, β2 and β5), each one presenting a nucleophilic N-terminus threonine residue [15]. The catalytic sites have different specificities: β1 presenting a caspase-like activity, β2 trypsin-like activity and β5 chymotrypsin-like activity [16]. This protease is involved in the most of intracellular processes of eukaryotic cells such as signal transduction, immune response, metabolism, cell death, besides protein turnover for cell quality control and regulatory purposes [17]. The most important proteasome inhibitors described in the literature can be divided into 5 classes: peptide aldehydes, peptide vinyl sulfones, peptide boronates, peptide epoxyketones and β-lactones [18]. Moreover, these inhibitors present unsuitable properties for future clinical investigation [19] and new classes of compounds capable of inhibiting proteasome are still required. In view of the importance of 20S PT and a lack of a study of organic selenium and tellurium compounds with thiol-independent proteases, we decided to explore the reactivity of organoselenuranes and organotelluranes (Fig. 1) against an O-nucleophilic protease (20S PT).
Section snippets
Results and discussion
The preparation of the organochalcogenanes 1–12 and their precursors was carried out from 1-phenylethanol derivatives as described previously [8].
The inhibitory profiles of organochalcogenanes against β1-caspase-like, β2-trypsin-like and β5-chymotrypsin-like sites of the mammalian 20S proteasome were determinated by an in vitro assay using 100 μmol L−1 of the compounds. The enzyme assays demonstrated that organochalcogenanes 1–12 are inactive against β1 and β5 sites (Fig. 2B and C). On the
Conclusions
The present results revealed that organochalcogenanes are a new class of 20S proteasome inhibitors, with an unusual high specificity to the β2 – trypsin-like catalytic site. Moreover, the organotelluranes presented superior potency in a close nanomolar scale (5–16 μM) than congeners, organoselenuranes. In cellular assays it was demonstrated that organoselenuranes are capable of maintaining efficiently their selectivities in inhibiting the β2 site, while organotelluranes became inactive under
Acknowledgment
The authors thank CNPq, CAPES and FAPESP for their financial support. The authors thank R. L. O. R. Cunha for helpful discussions.
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Present address: Departamento de Química, Universidade Federal do Paraná, Centro Politécnico – 81531-980, Curitiba, Brazil.