Tellurium Compounds:  Selective Inhibition of Cysteine Proteases and Model Reaction with Thiols

Abstract

Ammonium trichloro(dioxoethylene-O,O‘)tellurate (AS101) is an organotellurium(IV) compound that exhibits immunomodulation activity. In light of the unique Te(IV)−thiol chemistry, it was tested as a selective cysteine protease inhibitor. Although no inhibitory activity of serine-, metallo-, or aspartic proteases was observed, AS101 exhibited time- and concentration-dependent inactivation of cysteine proteases. The kinetic parameters of inactivation of papain were K i = 3.5 ± 2.0 μM and k i = (5.1 ± 0.4) × 10-2 min-1. The enzymatic activity could be recovered by treatment with thiols, indicating that the inactivation involves oxidation of the active-site thiol to a disulfide bond (Enz−S−S−R) or to a species containing a Te−S bond such as Enz−S−Te−S−R. Gel permeation chromatography established that the R group is a small molecule and excludes the possibility of dimerization of the enzyme itself. It was further established that some other Te(IV) derivatives could also inactivate cysteine proteases, while Te(VI) derivatives did not exhibit any such inhibitory activity. In order to understand the chemistry underlying the cysteine protease inactivation by AS101 and other organotellurium(IV) compounds, their interaction with the model compound cysteine was studied. While the Te(VI) derivatives did not interact with cysteine, all of the Te(IV) compounds interacted with 4 equiv of cysteine. The kinetics of this interaction is first order in Te and second order in thiol, yielding a third-order rate constant of ∼106 M-2 s-1, as determined for the interaction between AS101 with cysteine. The interactions between Te derivatives and cysteine in DMSO were followed by 125Te and 13C NMR. While Te(VI) compounds did not undergo any changes upon interaction with cysteine, on the basis of their 125Te NMR, the Te(IV) derivatives interacted with 4 equiv of cysteine, yielding new stable Te(IV) compounds. These compounds were tentatively designated as Te(cysteine)4 or its high-valence complex with other components in the reaction mixture. These results expand our understanding of tellurium chemistry and correlate well with its biological activity. Such knowledge can be applied for the development of novel biologically active tellurium compounds.

Enantioselective control of lattice and shape chirality in inorganic nanostructures using chiral biomolecules

“…These biomolecules proved to be very efficient reducing agents through the thiol group oxidation, as previously discussed for the case of Te(IV) species 32,33 . An additional reducing agent, hydrazine, was added, in some cases, immediately before or after the fast reduction by the biomolecule.…”

“…As the Te reduction mechanism proceeds through initial formation of a complex of Te(IV) with four thiolate molecules 32 , the kinetics of the reaction should depend on the structure of the ligand molecule, which affects the geometry and stability of this complex, and the way it allows assembly of Te atom dimers or oligomers. Reduction of Te(IV) by hydrazine was much slower than by the biomolecules and it is not dominant in early stages of the reduction process.…”

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

“…Experimental observations showed that tellurium(IV) compounds are irreversible inhibitors of cysteine proteases [28,31,72,73]. The inhibition occurs due to the formation of a Te(IV)-SG covalent bond between the electrophilic tellurium(IV) centre and the nucleophilic thiol group of the catalytic cysteine via the loss of a leaving group bound to the tellurium atom [31,32,47,48].…”

“…The most notable tellurium compound that exerts biological activity is found in the salt ammonium trichlorido (dioxyethylene-O,Oꞌ)tellurate, known as AS-101 ( Figure 1a) [25]. This low-molecular weight organotellurate is a potent immunomodulator [26] that has been in clinical trials for psoriasis [27], topical treatment for human papillomavirus [28], prevention of infertility in chemotherapy patients [29] and for inhibition of angiogenesis [24,30].…”

Crystallographic, DFT and docking (cathepsin B) studies on an organotellurium(IV) compound

“…In this context, the tellurium atom in a number of organotellurium compounds has been shown to bind sulphur at the Cys29 site thereby rendering the protein inactive [9][10][11][12]. The most promising tellurium-based therapeutic agent, ammonium trichloro (dioxoethylene-O,Oꞌ)tellurate (AS101), 2 in Fig.…”