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

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 cystcine protcase inhibitor. Although no inhibitory activity of serine-, metallo-, or aspartic proteases was observed, AS101 exhibited time- and concentration-dependent inactivation of cystcine proteases. The kinetic parameters of inactivalion 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 alsoimiclivate cysteinc 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 cystcine. 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 cysteinc 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(cysteinene)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.