TELLURIUM COMPOUNDS - SELECTIVE-INHIBITION OF CYSTEINE PROTEASES AND MODEL REACTION WITH THIOLS

Ammonium trichloro(dioxoethylene-O,O')tellurate (AS101) is an organote llurium(IV) compound that exhibits immunomodulation activity. In light of the unique Te(IV)-thiol chemistry, it was tested asa selective cys teine 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 kinet ic parameters of inactivation of papain were K-i = 3.5 +/- 2.0 mu M an d k(i) = (5.1 +/- 0.4) x 10(-2) min(-1). The enzymatic activity could be recovered by treatment with thiols, indicating that the inactivatio n 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. G el permeation chromatography established that the R group is a small m olecule and excludes the possibility of dimerization of the enzyme its elf. It was further established that some other Te(IV) derivatives cou ld also inactivate cysteine proteases, while Te(VI) derivatives did no t exhibit any such inhibitory activity. In order to understand the che mistry underlying the cysteine protease inactivation by AS101 and othe r organotellurium(IV) compounds, their interaction with the model comp ound cysteine was studied. While the Te(VI) derivatives did not intera ct 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 simila r to 10(6) 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 Te-125 and C-13 NMR. While Te(VI) compounds did not undergo any changes upon interaction with cysteine. on the basis of their Te-125 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 wi th other components in the reaction mixture. These results expand our understanding of tellurium chemistry and correlate well with its biolo gical activity. Such knowledge can be applied for the development of n ovel biologically active tellurium compounds.