Journal
BIOCHEMISTRY
Volume 42, Issue 35, Pages 10418-10428Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi0346188
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- NIGMS NIH HHS [GM62284, T32 GM07750] Funding Source: Medline
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Exploiting the principle of bivalent binding, we have designed symmetrical, bifunctional inhibitors to simultaneously occupy both active sites of cytosolic glutathione S-transferase, with enhanced specificity for the PI-I isoform. We have prepared two series of compounds that differ in their binding domains-the first is a series of bis-glutathione conjugates, and the second is a series of compounds each possessing two equivalents of Uniblue A, an analogue of Cibacron Blue. For each series, a monofunctional reference compound was also prepared to determine the relative advantage of the bivalent inhibitors. Within each series, the most potent inhibitors exhibited IC50 values 2 orders of magnitude lower than the relevant reference compounds. Moreover, within the bis-glutathionyl series, a 10-fold increase in selectivity was achieved for GST P1-1 over the A1-1 isoform. Isothermal titration calorimetry with a representative bis-glutathione conjugate and a monofunctional reference compound indicates that the bivalent inhibitor exhibits the expected increase in intrinsic affinity and decrease in stoichiometry relative to the monofunctional compound, supporting the overall design strategy.
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