ISOZYME SPECIFICITY OF NOVEL GLUTATHIONE-S-TRANSFERASE INHIBITORS

A systematically diversified set of peptide analogs of the reaction pr oduct of glutathione with an electrophilic substrate have been tested as isozyme-specific inhibitors of human glutathione-S-transferase (GST ). The potency of the best of the inhibitors is in the 0.5 to 20 micro molar range, with kinetics indicative of competitive inhibition with g lutathione at the active site. The specificity observed among three re combinant-derived GST isozymes at both low and high potency ranged fro m negligible to high (at least 20-fold over the next most sensitive is ozyme). These results define a novel strategy for the design of drugs targeting cells with elevated levels of particular GST isozymes, such as tumor cells for which elevated levels of GST are believed to be an important cause of chemotherapeutic drug resistance.